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Ferrari P, Schiavone ML, Scatena C, Nicolini A. Molecular Mechanisms and Therapeutic Strategies to Overcome Resistance to Endocrine Therapy and CDK4/6 Inhibitors in Advanced ER+/HER2- Breast Cancer. Int J Mol Sci 2025; 26:3438. [PMID: 40244377 PMCID: PMC11989623 DOI: 10.3390/ijms26073438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Revised: 04/01/2025] [Accepted: 04/04/2025] [Indexed: 04/18/2025] Open
Abstract
Approximately 70-80% of breast cancers are estrogen receptor-positive (ER+), with 65% of these cases also being progesterone receptor-positive (ER+PR+). In most cases of ER+ advanced breast cancer, endocrine therapy (ET) serves as the first-line treatment, utilizing various drugs that inhibit ER signaling. These include tamoxifen, a selective estrogen receptor modulator (SERM); fulvestrant, a selective estrogen receptor degrader (SERD); and aromatase inhibitors (AIs), which block estrogen synthesis. However, intrinsic or acquired hormone resistance eventually develops, leading to disease progression. The combination of ET with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) has been shown to significantly increase progression-free survival (PFS) and, in some cases, overall survival (OS). CDK4/6is works by arresting the cell cycle in the G1 phase, preventing DNA synthesis, and enhancing the efficacy of ET. This review highlights the key mechanisms of resistance to ET, whether used alone or in combination with biological agents, as well as emerging therapeutic strategies aimed at overcoming resistance. Addressing ET resistance remains a work in progress, and in the near future, better patient selection for different therapeutic approaches is expected through the identification of more precise biological and genetic markers. In particular, liquid biopsy may provide a real-time portrait of the disease, offering insights into mechanisms driving ET resistance and cancer progression.
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Affiliation(s)
- Paola Ferrari
- Department of Oncology, Pisa University Hospital, Via Roma 57, 56126 Pisa, Italy; (C.S.); (A.N.)
| | - Maria Luisa Schiavone
- Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy;
| | - Cristian Scatena
- Department of Oncology, Pisa University Hospital, Via Roma 57, 56126 Pisa, Italy; (C.S.); (A.N.)
- Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy;
| | - Andrea Nicolini
- Department of Oncology, Pisa University Hospital, Via Roma 57, 56126 Pisa, Italy; (C.S.); (A.N.)
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Neill NE, Mauro LA, Pennisi A. Novel Estrogen Receptor - Targeted Therapies in Hormone-Receptor Positive Breast Cancer. Curr Treat Options Oncol 2025; 26:302-312. [PMID: 40163189 DOI: 10.1007/s11864-025-01310-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2025] [Indexed: 04/02/2025]
Abstract
OPINION STATEMENT Endocrine therapy is the backbone of treatment for HR + /HER2- MBC. The introduction of novel endocrine-based therapies has changed the landscape of metastatic breast cancer care, with even more promising agents on the horizon. Given the consistent success in prolonging PFS and OS, CDK4/6 inhibitors should be used as first-line treatment. Once secondary resistance eventually develops after use of a CDK4/6 inhibitor, use of monotherapy with either AI or fulvestrant has shown poor outcome. For example, in the control group of the EMERALD trial, in which all the patients were required to have previously received a CDK4/6 inhibitor, median progression-free survival with endocrine therapy was only 1.9 months. Based on the emerging evidence, molecular profiling of tissue or liquid biopsy at progression of disease is crucial to select future therapy. For patients whose tumors harbor ESR1 mutations, oral SERDs are the preferred option. For those with PIK3CA or AKT1 mutation or PTEN inactivation, combination therapy with the AKT pathway inhibitor capivasertib is recommended. Alpelisib, the first AKT1 inhibitor approved in combination therapy with fulvestrant in PIK3CA mutated tumors only, is now less in favor given its challenging side effect profile. When mutations are not present, options include combination therapy with the mTOR inhibitor everolimus or changing endocrine therapy and continuing a CDK 4/6 inhibitor. In patients with short response to CDK4/6 inhibitors suggesting endocrine resistant disease, chemotherapy or antibody-drug conjugates should be considered. With better understanding of the mechanisms of resistance to CDK4/6 inhibitors, additional mutations could be identified and potentially targeted in order to provide individualized treatment options. Optimal sequencing of treatment options depends on several factors: (1) the presence of specific molecular aberrations; (2) previous treatment history, duration of response and patient's performance status; (3) balance between maximizing survival benefits with quality of life/toxicities; (4) disease burden. In the upcoming years, we anticipate FDA approvals for more of the SERD molecules both in monotherapy and in combination therapy which will continue to expand the options available for HR + /HER2- MBC patients.
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Affiliation(s)
- Nina E Neill
- Inova Schar Cancer Institute, Fairfax, Virginia, USA.
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Ji L, Chen J, He L, Zhang F, Deng Z, Lin J, Qi Z, Luo X, Giuliano AE, Cui X, Lin SL, Cui Y. Reversal of endocrine resistance via N6AMT1-NEDD4L pathway-mediated p110α degradation. Oncogene 2025; 44:530-544. [PMID: 39623076 PMCID: PMC11832415 DOI: 10.1038/s41388-024-03238-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 11/13/2024] [Accepted: 11/20/2024] [Indexed: 02/19/2025]
Abstract
Approximately 70% of breast cancer (BC) cases are luminal-type (estrogen receptor-positive, ER+), suitable for endocrine therapy with tamoxifen as the most commonly used drug. However, about 30% of these patients develop tamoxifen resistance due to various mechanisms, primarily involving PI3K pathway activation through mutations or unknown pathways. Here, we discover, via bioinformatics analysis and clinical samples, that N6 adenine-specific DNA methyltransferase 1 (N6AMT1) is highly expressed in luminal breast cancer but downregulated in tamoxifen-resistant (TamR) BC cells. ChIP-qPCR and luciferase reporter assays showed that FOXA1 binds to the N6AMT1 promoter and enhances its transcription. In TamR models, FOXA1 and N6AMT1 are downregulated, increasing p110α protein levels (but not mRNA), phospho-AKT levels, and tamoxifen resistance. In vivo, N6AMT1 overexpression enhanced tamoxifen sensitivity, while knockdown reduced it; this sensitivity could be restored with the p110α inhibitor A66. Clinically, decreased N6AMT1 expression correlates with poor prognosis in luminal BC patients. In TamR BC organoids, combining tamoxifen with A66 further reduced growth compared to either treatment alone. Mechanistically, increased p110α levels result from inhibited degradation by E3 ubiquitin ligase NEDD4L. These findings suggest N6AMT1 as a potential luminal breast cancer biomarker and highlight the N6AMT1-p110α pathway as a therapeutic target to sensitize cells to tamoxifen.
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Affiliation(s)
- Likeng Ji
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jiongyu Chen
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Lifang He
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Fan Zhang
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zihao Deng
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jiediao Lin
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zhaochang Qi
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Xi Luo
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Armando E Giuliano
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Xiaojiang Cui
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stanley Li Lin
- Department of Cell Biology, Shantou University Medical College, Shantou, Guangdong, China
| | - Yukun Cui
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China.
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4
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Laetsch TW, Ludwig K, Williams PM, Roy-Chowdhuri S, Patton DR, Coffey B, Reid JM, Piao J, Saguilig L, Alonzo TA, Berg SL, Mhlanga J, Fox E, Weigel BJ, Hawkins DS, Mooney MM, Takebe N, Tricoli JV, Janeway KA, Seibel NL, Parsons DW. Phase II Study of Samotolisib in Children and Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Pathway Alterations: Pediatric MATCH APEC1621D. JCO Precis Oncol 2024; 8:e2400258. [PMID: 39298693 PMCID: PMC11581706 DOI: 10.1200/po.24.00258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/03/2024] [Accepted: 07/29/2024] [Indexed: 09/22/2024] Open
Abstract
PURPOSE Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib. METHODS Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children. RESULTS A total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), PIK3CA (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m2/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children. CONCLUSION This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.
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Affiliation(s)
- Theodore W Laetsch
- Children's Hospital of Philadelphia/University of Pennsylvania, Philadelphia, PA
| | | | | | | | - David R Patton
- Center for Biomedical Informatics and Information Technology, NCI, NIH, Bethesda, MD
| | - Brent Coffey
- Center for Biomedical Informatics and Information Technology, NCI, NIH, Bethesda, MD
| | - Joel M Reid
- Mayo Clinic Comprehensive Cancer Center, Rochester, MN
| | - Jin Piao
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| | | | - Todd A Alonzo
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Stacey L Berg
- Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX
| | - Joyce Mhlanga
- Washington University School of Medicine, St Louis, MO
| | | | | | - Douglas S Hawkins
- Seattle Children's Hospital and University of Washington, Seattle, WA
| | - Margaret M Mooney
- Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD
| | - Naoko Takebe
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
| | - James V Tricoli
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
| | | | - Nita L Seibel
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
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Sutherland L, Lang J, Gonzalez-Juarbe N, Pickett BE. Secondary Analysis of Human Bulk RNA-Seq Dataset Suggests Potential Mechanisms for Letrozole Resistance in Estrogen-Positive (ER+) Breast Cancer. Curr Issues Mol Biol 2024; 46:7114-7133. [PMID: 39057065 PMCID: PMC11275280 DOI: 10.3390/cimb46070424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 06/26/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
Estrogen receptor-positive (ER+) breast cancer is common among postmenopausal women and is frequently treated with Letrozole, which inhibits aromatase from synthesizing estrogen from androgens. Decreased estrogen slows the growth of tumors and can be an effective treatment. The increase in Letrozole resistance poses a unique problem for patients. To better understand the underlying molecular mechanism(s) of Letrozole resistance, we reanalyzed transcriptomic data by comparing individuals who responded to Letrozole therapy (responders) to those who were resistant to treatment (non-responders). We identified SOX11 and S100A9 as two significant differentially expressed genes (DEGs) between these patient cohorts, with "PLK1 signaling events" being the most significant signaling pathway. We also identified PRDX4 and E2F8 gene products as being the top mechanistic transcriptional markers for ER+ treatment resistance. Many of the significant DEGs that we identified play a known role in ER+ breast cancer or other types of cancer, which partially validate our results. Several of the gene products we identified are novel in the context of ER+ breast cancer. Many of the genes that we identified warrant further research to elucidate the more specific molecular mechanisms of Letrozole resistance in this patient population and could potentially be used as prognostic markers with further wet lab validation. We anticipate that these findings could contribute to improved detection and therapeutic outcomes in aromatase-resistant ER+ breast cancer patients.
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Affiliation(s)
- Lincoln Sutherland
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; (L.S.); (J.L.)
| | - Jacob Lang
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; (L.S.); (J.L.)
| | - Norberto Gonzalez-Juarbe
- J. Craig Venter Institute, Rockville, MD 20850, USA;
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
| | - Brett E. Pickett
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; (L.S.); (J.L.)
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Cui Y, Ran R, Da Y, Zhang H, Jiang M, Qi X, Zhang W, Niu L, Zhou Y, Zhou C, Tang X, Wang K, Yan Y, Ren Y, Dong D, Zhou Y, Wang H, Gong J, Hu F, Zhao S, Zhang H, Zhang C, Yang J. The combination of breast cancer PDO and mini-PDX platform for drug screening and individualized treatment. J Cell Mol Med 2024; 28:e18374. [PMID: 38722288 PMCID: PMC11081008 DOI: 10.1111/jcmm.18374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 03/05/2024] [Accepted: 04/16/2024] [Indexed: 05/12/2024] Open
Abstract
The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient-derived organoids (PDOs) with mini-patient-derived xenografts (Mini-PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high-fidelity three-dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug-resistant breast cancer, we combined PDO and Mini-PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini-PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.
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Affiliation(s)
- Yuxin Cui
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Ran Ran
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Yanyan Da
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Center for Molecular Diagnosis and Precision MedicineThe First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Huiwen Zhang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Meng Jiang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Xin Qi
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Wei Zhang
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Ligang Niu
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Yuhui Zhou
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Can Zhou
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Xiaojiang Tang
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Ke Wang
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Yu Yan
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Yu Ren
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Danfeng Dong
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Yan Zhou
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Hui Wang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Jin Gong
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Fang Hu
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Shidi Zhao
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Huimin Zhang
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Chengsheng Zhang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Center for Molecular Diagnosis and Precision MedicineThe First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Jin Yang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
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Batra H, Mouabbi JA, Ding Q, Sahin AA, Raso MG. Lobular Carcinoma of the Breast: A Comprehensive Review with Translational Insights. Cancers (Basel) 2023; 15:5491. [PMID: 38001750 PMCID: PMC10670219 DOI: 10.3390/cancers15225491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/09/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
The second most common breast carcinoma, invasive lobular carcinoma, accounts for approximately 15% of tumors of breast origin. Its incidence has increased in recent times due in part to hormone replacement therapy and improvement in diagnostic modalities. Although believed to arise from the same cell type as their ductal counterpart, invasive lobular carcinomas (ILCs) are a distinct entity with different regulating genetic pathways, characteristic histologies, and different biology. The features most unique to lobular carcinomas include loss of E-Cadherin leading to discohesion and formation of a characteristic single file pattern on histology. Because most of these tumors exhibit estrogen receptor positivity and Her2 neu negativity, endocrine therapy has predominated to treat these tumors. However novel treatments like CDK4/6 inhibitors have shown importance and antibody drug conjugates may be instrumental considering newer categories of Her 2 Low breast tumors. In this narrative review, we explore multiple pathological aspects and translational features of this unique entity. In addition, due to advancement in technologies like spatial transcriptomics and other hi-plex technologies, we have tried to enlist upon the characteristics of the tumor microenvironment and the latest associated findings to better understand the new prospective therapeutic options in the current era of personalized treatment.
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Affiliation(s)
- Harsh Batra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Jason Aboudi Mouabbi
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Qingqing Ding
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (Q.D.); (A.A.S.)
| | - Aysegul A. Sahin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (Q.D.); (A.A.S.)
| | - Maria Gabriela Raso
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
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Raheem F, Karikalan SA, Batalini F, El Masry A, Mina L. Metastatic ER+ Breast Cancer: Mechanisms of Resistance and Future Therapeutic Approaches. Int J Mol Sci 2023; 24:16198. [PMID: 38003387 PMCID: PMC10671474 DOI: 10.3390/ijms242216198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/05/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Endocrine therapy is the main treatment for hormone receptor-positive (HR+) breast cancer. However, advanced tumors develop resistance to endocrine therapy, rendering it ineffective as the disease progresses. There are several molecular mechanisms of primary and secondary endocrine resistance. Resistance can develop due to either alteration of the estrogen receptor pathway (e.g., ESR1 mutations) or upstream growth factors signaling pathways (e.g., PI3K/Akt/mTOR pathway). Despite progress in the development of molecularly targeted anticancer therapies, the emergence of resistance remains a major limitation and an area of unmet need. In this article, we review the mechanisms of acquired endocrine resistance in HR+ advanced breast cancer and discuss current and future investigational therapeutic approaches.
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Affiliation(s)
| | | | | | - Aya El Masry
- Phoenix Country Day School, Paradise Valley, AZ 85253, USA
| | - Lida Mina
- Mayo Clinic, Phoenix, AZ 85054, USA; (F.R.)
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9
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Fu X, Pereira R, Liu CC, De Angelis C, Shea MJ, Nanda S, Qin L, Mitchell T, Cataldo ML, Veeraraghavan J, Sethunath V, Giuliano M, Gutierrez C, Győrffy B, Trivedi MV, Cohen O, Wagle N, Nardone A, Jeselsohn R, Rimawi MF, Osborne CK, Schiff R. High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer. Cell Rep 2023; 42:112821. [PMID: 37467106 DOI: 10.1016/j.celrep.2023.112821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 11/03/2022] [Accepted: 07/03/2023] [Indexed: 07/21/2023] Open
Abstract
Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome.
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Affiliation(s)
- Xiaoyong Fu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Resel Pereira
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chia-Chia Liu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Carmine De Angelis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Martin J Shea
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sarmistha Nanda
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lanfang Qin
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Tamika Mitchell
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Maria L Cataldo
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Jamunarani Veeraraghavan
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Vidyalakshmi Sethunath
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mario Giuliano
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Carolina Gutierrez
- Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, 1085 Budapest, Hungary; RCNS Cancer Biomarker Research Group, Institute of Enzymology, Magyar Tudósok körútja 2, 1117 Budapest, Hungary
| | - Meghana V Trivedi
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pharmacy Practice and Translational Research, University of Houston, Houston, TX 77204, USA; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204, USA
| | - Ofir Cohen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva 84105, Israel
| | - Nikhil Wagle
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Agostina Nardone
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA
| | - Rinath Jeselsohn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA
| | - Mothaffar F Rimawi
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - C Kent Osborne
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Rachel Schiff
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
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10
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Repeated exposure to 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) accelerates ligand-independent activation of estrogen receptors in long-term estradiol-deprived MCF-7 cells. Toxicol Lett 2023; 378:31-38. [PMID: 36863540 DOI: 10.1016/j.toxlet.2023.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 02/16/2023] [Accepted: 02/26/2023] [Indexed: 03/02/2023]
Abstract
It was previously identified that there may be an active metabolite of bisphenol A (BPA), 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP). An in vitro system was developed to detect MBP toxicity to the Michigan Cancer Foundation-7 (MCF-7) cells that had been repeatedly exposed to a low dose of the metabolite. MBP profoundly activated estrogen receptor (ER)-dependent transcription as a ligand, with an EC50 of 2.8 nM. Women are continuously exposed to numerous estrogenic environmental chemicals; but their susceptibility to these chemicals may be significantly altered after menopause. Long-term estrogen-deprived (LTED) cells, which display ligand-independent ER activation, are a postmenopausal breast cancer model derived from MCF-7 cells. In this study, we investigated the estrogenic effects of MBP on LTED cells in a repeated exposure in vitro model. The results suggest that i) nanomolar levels of MBP reciprocally disrupt the balanced expression of ERα and ERβ proteins, leading to the dominant expression of ERβ, ii) MBP stimulates ERs-mediated transcription without acting as an ERβ ligand, and iii) MBP utilizes mitogen-activated protein kinase and phosphatidylinositol-3 kinase signaling to evoke its estrogenic action. Moreover, the repeated exposure strategy was effective for detecting low-dose estrogenic-like effects caused by MBP in LTED cells.
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11
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Coimbra PPS, da Silva-e-Silva ACAG, Antonio ADS, Pereira HMG, da Veiga-Junior VF, Felzenszwalb I, Araujo-Lima CF, Teodoro AJ. Antioxidant Capacity, Antitumor Activity and Metabolomic Profile of a Beetroot Peel Flour. Metabolites 2023; 13:metabo13020277. [PMID: 36837895 PMCID: PMC9961284 DOI: 10.3390/metabo13020277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/19/2022] [Accepted: 12/23/2022] [Indexed: 02/17/2023] Open
Abstract
In this study, a beetroot peel flour was made, and its in vitro antioxidant activity was determined in aqueous (BPFw) and ethanolic (BPFe) extracts. The influence of BPFw on breast cancer cell viability was also determined. A targeted betalain profile was obtained using high-resolution Q-Extractive Plus Orbitrap mass spectrometry (Obrtitrap-HRMS) alongside untargeted chemical profiling of BPFw using Ultra-High-Performance Liquid Chromatography with High-Resolution Mass Spectrometry (UHPLC-HRMS). BPFw and BPFe presented satisfactory antioxidant activities, with emphasis on the total phenolic compounds and ORAC results for BPFw (301.64 ± 0.20 mg GAE/100 g and 3032.78 ± 55.00 µmol T/100 g, respectively). The MCF-7 and MDA-MB-231 breast cancer cells presented reductions in viability when treated with BPFw, showing dose-dependent behavior, with MDA-MB-231 also showing time-dependent behavior. The chemical profiling of BPFw led to the identification of 9 betalains and 59 other compounds distributed amongst 28 chemical classes, with flavonoids and their derivates and coumarins being the most abundant. Three forms of betalain generated via thermal degradation were identified. However, regardless of thermal processing, the BPF still presented satisfactory antioxidant and anticancer activities, possibly due to synergism with other identified molecules with reported anticancer activities via different metabolic pathways.
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Affiliation(s)
- Pedro Paulo Saldanha Coimbra
- Food and Nutrition Graduate Program, Federal University of Rio de Janeiro State, Rio de Janeiro 21941-901, Brazil
- Laboratory of Environmental Mutagenicity, Department of Biophysics and Biometry, Rio de Janeiro State University, Rio de Janeiro 20550-013, Brazil
| | | | - Ananda da Silva Antonio
- Laboratory for the Support of Technological Development, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - Henrique Marcelo Gualberto Pereira
- Laboratory for the Support of Technological Development, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | | | - Israel Felzenszwalb
- Laboratory of Environmental Mutagenicity, Department of Biophysics and Biometry, Rio de Janeiro State University, Rio de Janeiro 20550-013, Brazil
| | - Carlos Fernando Araujo-Lima
- Food and Nutrition Graduate Program, Federal University of Rio de Janeiro State, Rio de Janeiro 21941-901, Brazil
- Laboratory of Environmental Mutagenicity, Department of Biophysics and Biometry, Rio de Janeiro State University, Rio de Janeiro 20550-013, Brazil
- Department of Genetics and Molecular Biology, Federal University of Rio de Janeiro State, Rio de Janeiro 21941-901, Brazil
- Correspondence: (C.F.A.-L.); (A.J.T.)
| | - Anderson Junger Teodoro
- Food and Nutrition Graduate Program, Federal University of Rio de Janeiro State, Rio de Janeiro 21941-901, Brazil
- Department of Nutrition and Dietetics, Faculty of Nutrition, Fluminense Federal University, Rio de Janeiro 24020-141, Brazil
- Correspondence: (C.F.A.-L.); (A.J.T.)
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12
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Marra A, Trapani D, Ferraro E, Curigliano G. Mechanisms of Endocrine Resistance in Hormone Receptor-Positive Breast Cancer. Cancer Treat Res 2023; 188:219-235. [PMID: 38175348 DOI: 10.1007/978-3-031-33602-7_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Hormone receptor-positive (HR+) breast cancer (BC) accounts for approximately 70% of all breast invasive tumors. Endocrine therapy (ET) represents the standard treatment for HR + BC. Most patients, however, eventually develop resistance to ET, which limits their effectiveness and poses a major challenge for the management of HR + BC. Several mechanisms that contribute to ET resistance have been described. One of the most common mechanisms is the upregulation of alternative signaling pathways that can bypass estrogen dependency, such as activation of the PI3K/Akt/mTOR as well as mitogen-activated protein kinase (MAPK) and the insulin-like growth factor 1 receptor (IGF-1R) pathways. Another common mechanism of endocrine resistance is the acquisition of activating mutations of ESR1, which encodes for the estrogen receptor, that lead to structural changes of the receptor, prevent the binding to anti-estrogen drugs and result in constitutive activation of the receptor, even in the absence of estrogens. Epigenetic changes, such as DNA methylation and histone modifications, can also contribute to ET resistance by altering the expression of genes that are involved in estrogen signaling. Understanding the mechanisms of resistance to ET is crucial for the development of new therapies that can overcome resistance and improve outcomes for patients with HR + BC.
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Affiliation(s)
- Antonio Marra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy.
| | - Dario Trapani
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
| | - Emanuela Ferraro
- Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hematology, University of Milan, Milan, Italy
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13
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Wang X, Jiang W, Du Y, Zhu D, Zhang J, Fang C, Yan F, Chen ZS. Targeting feedback activation of signaling transduction pathways to overcome drug resistance in cancer. Drug Resist Updat 2022; 65:100884. [DOI: 10.1016/j.drup.2022.100884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/05/2022] [Accepted: 10/09/2022] [Indexed: 11/03/2022]
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14
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Hisada T, Kondo N, Wanifuchi-Endo Y, Osaga S, Fujita T, Asano T, Uemoto Y, Nishikawa S, Katagiri Y, Terada M, Kato A, Sugiura H, Okuda K, Kato H, Komura M, Morita S, Takahashi S, Toyama T. Co-expression effect of LLGL2 and SLC7A5 to predict prognosis in ERα-positive breast cancer. Sci Rep 2022; 12:16515. [PMID: 36192404 PMCID: PMC9529905 DOI: 10.1038/s41598-022-20225-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 09/09/2022] [Indexed: 11/09/2022] Open
Abstract
Lethal giant larvae homolog 2 (LLGL2) and solute carrier family 7 member 5 (SLC7A5) have been reported to be involved in resistance to endocrine therapy. This study aimed to assess the effects of LLGL2/SLC7A5 co-expression in predicting prognosis and response to tamoxifen therapy in ERα-positive breast cancer patients according to LLGL2/SLC7A5 mRNA and protein expression in long-term follow-up invasive breast cancer tissues. We identified that low LLGL2/SLC7A5 mRNA co-expression (LLGL2low/SLC7A5low) was associated with disease-free survival (DFS) compared with other combination groups in all breast cancer patients. In ERα-positive breast cancer patients, LLGL2low/SLC7A5low showed longer DFS and overall survival (OS) compared with LLGL2high/SLC7A5high and a positive trend of longer survival compared with the other combination groups. We also observed that LLGL2low/SLC7A5low showed longer survival compared with LLGL2high/SLC7A5high in ERα-positive breast cancer patients receiving adjuvant tamoxifen therapy. Multivariate analysis demonstrated that LLGL2low/SLC7A5low was an independent favorable prognostic factor of both DFS and OS, not only in all breast cancer patients, but also in ERα-positive breast cancer patients. High co-expression of LLGL2 and SLC7A5 protein showed a positive trend of shorter survival. Our study showed that co-expression of LLGL2 and SLC7A5 mRNA is a promising candidate biomarker in early breast cancer patients.
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Affiliation(s)
- Tomoka Hisada
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Naoto Kondo
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Yumi Wanifuchi-Endo
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Satoshi Osaga
- Clinical Research Management Center, Nagoya City University Hospital, Nagoya, Aichi, Japan
| | - Takashi Fujita
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Tomoko Asano
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Yasuaki Uemoto
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Sayaka Nishikawa
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Yusuke Katagiri
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Mitsuo Terada
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Akiko Kato
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Hiroshi Sugiura
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.,Department of Breast and Endocrine Surgery, Nagoya City University West Medical Center, Nagoya, Aichi, Japan
| | - Katsuhiro Okuda
- Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Hiroyuki Kato
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Masayuki Komura
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Tatsuya Toyama
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
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15
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Arruabarrena-Aristorena A, Toska E. Epigenetic Mechanisms Influencing Therapeutic Response in Breast Cancer. Front Oncol 2022; 12:924808. [PMID: 35774123 PMCID: PMC9239340 DOI: 10.3389/fonc.2022.924808] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/05/2022] [Indexed: 12/13/2022] Open
Abstract
The majority of breast cancers are estrogen receptor (ER)+ and agents targeting the ER signaling pathway have markedly increased survival for women with breast cancer for decades. However, therapeutic resistance eventually emerges, especially in the metastatic setting. In the past decade disrupted epigenetic regulatory processes have emerged as major contributors to carcinogenesis in many cancer types. Aberrations in chromatin modifiers and transcription factors have also been recognized as mediators of breast cancer development and therapeutic outcome, and new epigenetic-based therapies in combination with targeted therapies have been proposed. Here we will discuss recent progress in our understanding of the chromatin-based mechanisms of breast tumorigenesis, how these mechanisms affect therapeutic response to standard of care treatment, and discuss new strategies towards therapeutic intervention to overcome resistance.
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Affiliation(s)
- Amaia Arruabarrena-Aristorena
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- Traslational Prostate Cancer Research Lab, CIC bioGUNE-Basurto, Biocruces Bizkaia Health Research Institute, Derio, Spain
| | - Eneda Toska
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, United States
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16
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Cheng GJ, Leung EY, Singleton DC. In vitro breast cancer models for studying mechanisms of resistance to endocrine therapy. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:297-320. [PMID: 36045910 PMCID: PMC9400723 DOI: 10.37349/etat.2022.00084] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/24/2022] [Indexed: 11/19/2022] Open
Abstract
The development of endocrine resistance is a common reason for the failure of endocrine therapies in hormone receptor-positive breast cancer. This review provides an overview of the different types of in vitro models that have been developed as tools for studying endocrine resistance. In vitro models include cell lines that have been rendered endocrine-resistant by ex vivo treatment; cell lines with de novo resistance mechanisms, including genetic alterations; three-dimensional (3D) spheroid, co-culture, and mammosphere techniques; and patient-derived organoid models. In each case, the key discoveries, different analysis strategies that are suitable, and strengths and weaknesses are discussed. Certain recently developed methodologies that can be used to further characterize the biological changes involved in endocrine resistance are then emphasized, along with a commentary on the types of research outcomes that using these techniques can support. Finally, a discussion anticipates how these recent developments will shape future trends in the field. We hope this overview will serve as a useful resource for investigators that are interested in understanding and testing hypotheses related to mechanisms of endocrine therapy resistance.
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Affiliation(s)
- Gary J. Cheng
- Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
| | - Euphemia Y. Leung
- Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1023, New Zealand
- Department of Molecular Medicine and Pathology, The University of Auckland, Auckland 1023, New Zealand
| | - Dean C. Singleton
- Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1023, New Zealand
- Department of Molecular Medicine and Pathology, The University of Auckland, Auckland 1023, New Zealand
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17
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Bick G, Zhang J, Lower EE, Zhang X. Transcriptional coactivator MED1 in the interface of anti-estrogen and anti-HER2 therapeutic resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:498-510. [PMID: 35800368 PMCID: PMC9255246 DOI: 10.20517/cdr.2022.33] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/30/2022] [Accepted: 04/02/2022] [Indexed: 11/18/2022]
Abstract
Breast cancer is one of the most common cancer and leading causes of death in women in the United States and Worldwide. About 90% of breast cancers belong to ER+ or HER2+ subtypes and are driven by key breast cancer genes Estrogen Receptor and HER2, respectively. Despite the advances in anti-estrogen (endocrine) and anti-HER2 therapies for the treatment of these breast cancer subtypes, unwanted side effects, frequent recurrence and resistance to these treatments remain major clinical challenges. Recent studies have identified ER coactivator MED1 as a key mediator of ER functions and anti-estrogen treatment resistance. Interestingly, MED1 is also coamplified with HER2 and activated by the HER2 signaling cascade, and plays critical roles in HER2-mediated tumorigenesis and response to anti-HER2 treatment as well. Thus, MED1 represents a novel crosstalk point of the HER2 and ER pathways and a highly promising new therapeutic target for ER+ and HER2+ breast cancer treatment. In this review, we will discuss the recent progress on the role of this key ER/HER2 downstream effector MED1 in breast cancer therapy resistance and our development of an innovative RNA nanotechnology-based approach to target MED1 for potential future breast cancer therapy to overcome treatment resistance.
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Affiliation(s)
- Gregory Bick
- Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Jasmine Zhang
- Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Elyse E. Lower
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. ,University of Cincinnati Cancer Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Xiaoting Zhang
- Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.,Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. ,University of Cincinnati Cancer Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.,Correspondence to: Prof. Xiaoting Zhang, Professor and Thomas Boat Endowed Chair, Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267, USA. E-mail:
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18
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Fuso P, Muratore M, D’Angelo T, Paris I, Carbognin L, Tiberi G, Pavese F, Duranti S, Orlandi A, Tortora G, Scambia G, Fabi A. PI3K Inhibitors in Advanced Breast Cancer: The Past, The Present, New Challenges and Future Perspectives. Cancers (Basel) 2022; 14:2161. [PMID: 35565291 PMCID: PMC9103982 DOI: 10.3390/cancers14092161] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 12/24/2022] Open
Abstract
Breast cancer is the leading cause of death in the female population and despite significant efforts made in diagnostic approaches and treatment strategies adopted for advanced breast cancer, the disease still remains incurable. Therefore, development of more effective systemic treatments constitutes a crucial need. Recently, several clinical trials were performed to find innovative predictive biomarkers and to improve the outcome of metastatic breast cancer through innovative therapeutic algorithms. In the pathogenesis of breast cancer, the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) axis is a key regulator of cell proliferation, growth, survival, metabolism, and motility, making it an interest and therapeutic target. Nevertheless, the PI3K/AKT/mTOR cascade includes a complex network of biological events, needing more sophisticated approaches for their use in cancer treatment. In this review, we described the rationale for targeting the PI3K pathway, the development of PI3K inhibitors and the future treatment directions of different breast cancer subtypes in the metastatic setting.
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Affiliation(s)
- Paola Fuso
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Margherita Muratore
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Tatiana D’Angelo
- Comprehensive Cancer Center, Unit of Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (T.D.); (A.O.); (G.T.)
| | - Ida Paris
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Luisa Carbognin
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Giordana Tiberi
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Francesco Pavese
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Simona Duranti
- Scientific Directorate, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
| | - Armando Orlandi
- Comprehensive Cancer Center, Unit of Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (T.D.); (A.O.); (G.T.)
| | - Giampaolo Tortora
- Comprehensive Cancer Center, Unit of Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (T.D.); (A.O.); (G.T.)
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giovanni Scambia
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
- Scientific Directorate, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
- Istituto di Ginecologia e Ostetricia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Alessandra Fabi
- Precision Medicine in Breast Cancer Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
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19
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Skolariki A, D’Costa J, Little M, Lord S. Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:172-199. [PMID: 36046843 PMCID: PMC9400772 DOI: 10.37349/etat.2022.00078] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 02/11/2022] [Indexed: 01/06/2023] Open
Abstract
The majority of breast cancers express the estrogen receptor (ER) and for this group of patients, endocrine therapy is the cornerstone of systemic treatment. However, drug resistance is common and a focus for breast cancer preclinical and clinical research. Over the past 2 decades, the PI3K/Akt/mTOR axis has emerged as an important driver of treatment failure, and inhibitors of mTOR and PI3K are now licensed for the treatment of women with advanced ER-positive breast cancer who have relapsed on first-line hormonal therapy. This review presents the preclinical and clinical data that led to this new treatment paradigm and discusses future directions.
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Affiliation(s)
- Aglaia Skolariki
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
| | - Jamie D’Costa
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
| | - Martin Little
- Department of Oncology, Churchill Hospital, OX3 7LE Oxford, UK
| | - Simon Lord
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
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20
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Eteleeb AM, Thunuguntla PK, Gelev KZ, Tang CY, Rozycki EB, Miller A, Lei JT, Jayasinghe RG, Dang HX, White NM, Reis-Filho JS, Mardis ER, Ellis MJ, Ding L, Silva-Fisher JM, Maher CA. LINC00355 regulates p27 KIP expression by binding to MENIN to induce proliferation in late-stage relapse breast cancer. NPJ Breast Cancer 2022; 8:49. [PMID: 35418131 PMCID: PMC9007952 DOI: 10.1038/s41523-022-00412-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 03/02/2022] [Indexed: 12/13/2022] Open
Abstract
Late-stage relapse (LSR) in patients with breast cancer (BC) occurs more than five years and up to 10 years after initial treatment and has less than 30% 5-year relative survival rate. Long non-coding RNAs (lncRNAs) play important roles in BC yet have not been studied in LSR BC. Here, we identify 1127 lncRNAs differentially expressed in LSR BC via transcriptome sequencing and analysis of 72 early-stage and 24 LSR BC patient tumors. Decreasing expression of the most up-regulated lncRNA, LINC00355, in BC and MCF7 long-term estrogen deprived cell lines decreases cellular invasion and proliferation. Subsequent mechanistic studies show that LINC00355 binds to MENIN and changes occupancy at the CDKN1B promoter to decrease p27Kip. In summary, this is a key study discovering lncRNAs in LSR BC and LINC00355 association with epigenetic regulation and proliferation in BC.
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Affiliation(s)
- Abdallah M Eteleeb
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Prasanth K Thunuguntla
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Kyla Z Gelev
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Emily B Rozycki
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Alexander Miller
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Reyka G Jayasinghe
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
- The McDonnell Genome Institute, St. Louis, MO, USA
| | - Ha X Dang
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
- The McDonnell Genome Institute, St. Louis, MO, USA
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Nicole M White
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Elaine R Mardis
- Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA
| | | | - Li Ding
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
- The McDonnell Genome Institute, St. Louis, MO, USA
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Jessica M Silva-Fisher
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
| | - Christopher A Maher
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
- The McDonnell Genome Institute, St. Louis, MO, USA.
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, USA.
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21
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Dhakal A, Acharya L, O’Regan R, Gandhi S, Falkson C. PI3Kinase Inhibition in Hormone Receptor-Positive Breast Cancer. Int J Mol Sci 2021; 22:ijms222111878. [PMID: 34769309 PMCID: PMC8584833 DOI: 10.3390/ijms222111878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/27/2021] [Accepted: 10/29/2021] [Indexed: 11/16/2022] Open
Abstract
Derangement of the phosphatidylinositol-3 kinase (PI3K) pathway is implicated in several subtypes of breast cancers. Mutation or upregulation of PI3K enhances cancer cells’ survival, proliferation, and ability to metastasize, making it an attractive molecular target for systemic therapy. PI3K has four isoforms, and several drugs targeting individual isoforms or pan-PI3K have been or are currently being investigated in clinical trials. However, the search for an effective PI3K inhibitor with a robust therapeutic effect and reasonable safety profile for breast cancer treatment remains elusive. This review focuses on the recently completed and ongoing clinical trials involving PI3K inhibitors as mono- or combination therapy in breast cancer. We review the salient findings of clinical trials, the therapeutic efficacy of PI3K inhibitors, and reported adverse effects leading to treatment discontinuation. Lastly, we discuss the challenges and potential opportunities associated with adopting PI3K inhibitors in the clinic.
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Affiliation(s)
- Ajay Dhakal
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA;
| | - Luna Acharya
- Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA;
| | - Ruth O’Regan
- Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA;
| | - Shipra Gandhi
- Roswell Park Cancer Institute, Buffalo, NY 14203, USA;
| | - Carla Falkson
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA;
- Correspondence:
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22
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Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res 2021; 23:85. [PMID: 34392831 PMCID: PMC8365900 DOI: 10.1186/s13058-021-01462-3] [Citation(s) in RCA: 168] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 07/20/2021] [Indexed: 11/10/2022] Open
Abstract
In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone of therapy, estrogen deprivation by aromatase inhibition. How these mutations affect tumor sensitivity to established and novel therapies are active areas of research. These therapies include estrogen receptor-targeting agents, such as selective estrogen receptor modulators, covalent antagonists, and degraders (including tamoxifen, fulvestrant, and novel agents), and combination therapies, such as endocrine therapy plus CDK4/6, PI3K, or mTORC1 inhibition. In this review, we summarize existing knowledge surrounding the mechanisms of action of ESR1 mutations and roles in resistance to aromatase inhibition. We then analyze the recent literature on how ESR1 mutations affect outcomes in estrogen receptor-targeting and combination therapies. For estrogen receptor-targeting therapies such as tamoxifen and fulvestrant, ESR1 mutations cause relative resistance in vitro but do not clearly lead to resistance in patients, making novel agents in this category promising. Regarding combination therapies, ESR1 mutations nullify any aromatase inhibitor component of the combination. Thus, combinations using endocrine alternatives to aromatase inhibition, or combinations where the non-endocrine component is efficacious as monotherapy, are still effective against ESR1 mutations. These results emphasize the importance of investigating combinatorial resistance, challenging as these efforts are. We also discuss future directions and open questions, such as studying the differences among distinct ESR1 mutations, asking how to adjust clinical decisions based on molecular surveillance testing, and developing novel therapies that are effective against ESR1 mutations.
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Affiliation(s)
- Jamie O Brett
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Laura M Spring
- Harvard Medical School, Boston, MA, USA
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02114, USA
| | - Aditya Bardia
- Harvard Medical School, Boston, MA, USA
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02114, USA
| | - Seth A Wander
- Harvard Medical School, Boston, MA, USA.
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02114, USA.
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23
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Song Y, Zheng C, Tao Y, Huang R, Zhang Q. N6-Methyladenosine Regulators Are Involved in the Progression of and Have Clinical Impact on Breast Cancer. Med Sci Monit 2021; 27:e929615. [PMID: 34349094 PMCID: PMC8353996 DOI: 10.12659/msm.929615] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background N6-methyladenosine (m6A) modification has been widely studied in various cancers, and m6A regulators, such as METTL3, METTL14, WTAP, and YTHDF1, play crucial roles in breast cancer. However, a comprehensive study of m6A regulators in breast cancer is still lacking. Material/Methods Expression data of m6A regulators and clinicopathological information were acquired from The Cancer Genome Atlas (TCGA) program. Protein interaction was collected from the STRING database. Data on tumor purity and correlation among m6A regulators were obtained from the TIMER database. LASSO, consensus clustering, and gene set enrichment analysis (GSEA) were used to evaluate the role of m6A regulators. Moreover, the prognostic value of m6A-related genomic targets in breast cancer was analyzed by Kaplan-Meier analysis and Cox regression models. Results We found most m6A regulators were associated with key clinicopathological parameters, such as tumor staging, Nottingham prognostic index (NPI), and cellularity. Also, consensus clustering analysis-based grouping could effectively predict patients’ overall survival. Correlation analysis also showed that these regulators interacted with each other. Patients were further split into a high-risk group and low-risk group based on Cox and LASSO analysis. High-risk patients had a significantly worse overall survival than did low-risk patients. Moreover, AKT1 and MYC were enriched in patients in the high-risk group, according to GSEA analysis. The patients in the high-risk group also displayed resistance to chemoradiotherapy or hormone therapy. Conclusions The m6A regulators are critical participants in the development and progression of breast cancer and are likely to be used to predict prognosis and develop treatment strategies.
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Affiliation(s)
- Yanni Song
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China (mainland).,Department of Plastic and Cosmetic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Chaojing Zheng
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Yangbao Tao
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Rui Huang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Qian Zhang
- Department of Colorectal Surgery, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China (mainland)
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24
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Abstract
Approximately 70% of invasive breast cancers have some degree of dependence on the estrogen hormone for cell proliferation and growth. These tumors have estrogen and/or progesterone receptors (ER/PR+), generally referred to as hormone receptor positive (HR+) tumors, as indicated by the presence of positive staining and varying intensity levels of estrogen and/or progesterone receptors on immunohistochemistry. Therapies that inhibit ER signaling pathways, such as aromatase inhibitors (letrozole, anastrozole, exemestane), selective ER modulators (tamoxifen), and ER down-regulators (fulvestrant), are the mainstays of treatment for hormone-receptor-positive breast cancers. However, de novo or acquired resistance to ER targeted therapies is present in many tumors, leading to disease progression. The PI3K/AKT/mTOR pathway is implicated in sustaining endocrine resistance and has become the target of many new drugs for ER+ breast cancer. This article reviews the function of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway and the various classes of PI3K pathway inhibitors that have been developed to disrupt this pathway signaling for the treatment of hormone-receptor-positive breast cancer.
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MESH Headings
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Breast Neoplasms/diagnosis
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors
- Class I Phosphatidylinositol 3-Kinases/genetics
- Class I Phosphatidylinositol 3-Kinases/metabolism
- DNA Mutational Analysis
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Female
- Humans
- Mutation
- Neoplasm Recurrence, Local/diagnosis
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Neoplasm Staging
- Phosphoinositide-3 Kinase Inhibitors/metabolism
- Proto-Oncogene Proteins c-akt/antagonists & inhibitors
- Proto-Oncogene Proteins c-akt/metabolism
- Receptors, Estrogen/antagonists & inhibitors
- Receptors, Estrogen/metabolism
- Receptors, Progesterone/antagonists & inhibitors
- Receptors, Progesterone/metabolism
- Signal Transduction/drug effects
- Signal Transduction/genetics
- TOR Serine-Threonine Kinases/antagonists & inhibitors
- TOR Serine-Threonine Kinases/metabolism
- Treatment Outcome
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Affiliation(s)
- Sara E Nunnery
- Breast Cancer Program, Division of Hematology/Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN, 37232-6307, USA
| | - Ingrid A Mayer
- Breast Cancer Program, Division of Hematology/Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN, 37232-6307, USA.
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25
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Castel P, Toska E, Engelman JA, Scaltriti M. The present and future of PI3K inhibitors for cancer therapy. NATURE CANCER 2021; 2:587-597. [PMID: 35118422 PMCID: PMC8809509 DOI: 10.1038/s43018-021-00218-4] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
Phosphoinositide-3- kinase (PI3K) signaling regulates cellular proliferation, survival and metabolism, and its aberrant activation is one of the most frequent oncogenic events across human cancers. In the last few decades, research focused on the development of PI3K inhibitors, from preclinical tool compounds to the highly specific medicines approved to treat patients with cancer. Herein we discuss current paradigms for PI3K inhibitors in cancer therapy, focusing on clinical data and mechanisms of action. We also discuss current limitations in the use of PI3K inhibitors including toxicities and mechanisms of resistance, with specific emphasis on approaches aimed to improve their efficacy.
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Affiliation(s)
- Pau Castel
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Eneda Toska
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA
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26
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High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer. Oncogene 2021; 40:3408-3421. [PMID: 33875787 PMCID: PMC8122072 DOI: 10.1038/s41388-021-01782-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/11/2021] [Accepted: 04/06/2021] [Indexed: 02/02/2023]
Abstract
Estrogen receptor alpha (ER)-positive breast cancer is commonly treated with endocrine therapies, including antiestrogens that bind and inhibit ER activity, and aromatase inhibitors that suppress estrogen biosynthesis to inhibit estrogen-dependent ER activity. Paradoxically, treatment with estrogens such as 17b-estradiol can also be effective against ER+ breast cancer. Despite the known efficacy of estrogen therapy, the lack of a predictive biomarker of response and understanding of the mechanism of action have contributed to its limited clinical use. Herein, we demonstrate that ER overexpression confers resistance to estrogen deprivation through ER activation in human ER+ breast cancer cells and xenografts grown in mice. However, ER overexpression and the associated high levels of ER transcriptional activation converted 17b-estradiol from a growth-promoter to a growth-suppressor, offering a targetable therapeutic vulnerability and a potential means of identifying patients likely to benefit from estrogen therapy. Since ER+ breast cancer cells and tumors ultimately developed resistance to continuous estrogen deprivation or continuous 17b-estradiol treatment, we tested schedules of alternating treatments. Oscillation of ER activity through cycling of 17b-estradiol and estrogen deprivation provided long-term control of patient-derived xenografts, offering a novel endocrine-only strategy to manage ER+ breast cancer.
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27
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Dong C, Wu J, Chen Y, Nie J, Chen C. Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer. Front Pharmacol 2021; 12:628690. [PMID: 33790792 PMCID: PMC8005514 DOI: 10.3389/fphar.2021.628690] [Citation(s) in RCA: 200] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/18/2021] [Indexed: 12/16/2022] Open
Abstract
Although chemotherapy, targeted therapy and endocrine therapy decrease rate of disease recurrence in most breast cancer patients, many patients exhibit acquired resistance. Hyperactivation of the PI3K/AKT/mTOR pathway is associated with drug resistance and cancer progression. Currently, a number of drugs targeting PI3K/AKT/mTOR are being investigated in clinical trials by combining them with standard therapies to overcome acquired resistance in breast cancer. In this review, we summarize the critical role of the PI3K/AKT/mTOR pathway in drug resistance, the development of PI3K/AKT/mTOR inhibitors, and strategies to overcome acquired resistance to standard therapies in breast cancer.
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Affiliation(s)
- Chao Dong
- Department of the Second Medical Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital, Kunming, China
| | - Jiao Wu
- Department of the Second Medical Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital, Kunming, China
| | - Yin Chen
- Department of Urology, Changhai Hospital, Navy Medical University, Shanghai, China
| | - Jianyun Nie
- Department of the Third Breast Surgery, The 3rd Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital, Kunming, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
- KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
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28
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Go RE, Kim CW, Lee SM, Lee HK, Choi KC. Fenhexamid induces cancer growth and survival via estrogen receptor-dependent and PI3K-dependent pathways in breast cancer models. Food Chem Toxicol 2021; 149:112000. [PMID: 33484789 DOI: 10.1016/j.fct.2021.112000] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 12/15/2020] [Accepted: 01/14/2021] [Indexed: 12/14/2022]
Abstract
Fenhexamid (Fen), a fungicide used to treat gray mold of fruits and vegetables, is reported to function as an endocrine disrupting chemical via the estrogen receptors (ER), despite low-toxicity of the pesticide. In this study, we elucidated that the disrupting effects of Fen are exerted via the ER and phosphatidylinositol 3-kinase (PI3K) pathways in breast cancer models. The WST assay, live cell monitoring, cell cycle analysis, colony formation assay, apoptotic analysis by JC-1 dyeing, and Western blot analysis were applied in ER positive MCF-7 and ER negative MDA-MB-231 breast cancer cells, after exposure to 17β-estradiol (E2), Fen, ICI 182,780 (ICI; an ER antagonist) and/or Pictilisib (Pic; a PI3K inhibitor). Exposure to E2 and Fen induced the cell growth and survival ability of MCF-7 cells by increasing the S-phase cells and regulating the cell cycle-related proteins (Cyclin D1 and E1, p21 and p27). In addition, E2 and Fen treatment resulted in elevated levels of the survival-related proteins (Survivin and PCNA), and inhibited apoptosis by increasing the mitochondrial membrane potential and regulating the apoptosis-related proteins (BAX, BCL-2, and Caspase-9). These changes were reversed to the same level as the control group when exposed to their respective inhibitors, thereby indicating that the changes are exerted via the ER and PI3K pathways. In particular, co-treatment with these inhibitors induced greater inhibition than single treatment. Conversely, no alterations were observed in the ER-negative MDA-MB-231 breast cancer cells. Taken together, these results indicate that Fen promotes the growth of breast cancer cells via the ER and/or PI3K pathways, similar to the E2 mechanism. Although a relatively safe pesticide, Fen possibly exerts its influence as an endocrine disrupting chemical in ER-positive breast cancer cells via the ER and PI3K pathways.
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Affiliation(s)
- Ryeo-Eun Go
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Cho-Won Kim
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Sung-Moo Lee
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Hong Kyu Lee
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
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Mavratzas A, Marmé F. Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations. Future Oncol 2021; 17:13-36. [DOI: 10.2217/fon-2020-0464] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Since the US FDA approval of everolimus/exemestane in July 2012, and of the first CDK 4/6 inhibitor, palbociclib, combined with endocrine treatment in February 2015, a third class of therapeutic compounds, the PI3K inhibitors, has been introduced to the arsenal of targeted therapies overcoming endocrine resistance in hormone receptor-positive metastatic breast cancer. Alpelisib (PIQRAY®) is the first of these novel agents yielding promising clinical results, giving an impetus to further development of tailored endocrine anticancer treatments. Herein, we review its pharmacodynamic and pharmacokinetic properties, safety and efficacy data, as well as Phase III SOLAR-1 trial, prompting FDA approval of alpelisib in hormone receptor-positive metastatic breast cancer harboring PIK3CA mutations. Furthermore, implications for clinical use and current research will also be discussed.
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Affiliation(s)
- Athanasios Mavratzas
- Department of Obstetrics & Gynecology Mannheim, Section of Conservative Gynecologic Oncology, Experimental & Translational Gynecologic Oncology, Medical Faculty Mannheim of University Heidelberg University Hospital, Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Frederik Marmé
- Department of Obstetrics & Gynecology Mannheim, Section of Conservative Gynecologic Oncology, Experimental & Translational Gynecologic Oncology, Medical Faculty Mannheim of University Heidelberg University Hospital, Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
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Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer. Nat Commun 2020; 11:5488. [PMID: 33127913 PMCID: PMC7599336 DOI: 10.1038/s41467-020-19291-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 10/06/2020] [Indexed: 12/31/2022] Open
Abstract
The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER+ breast cancers. Mechanistically, the proline-rich motif-mediated interaction of PRR11 with the p85α regulatory subunit of PI3K suppresses p85 homodimerization, thus enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K. PRR11-amplified breast cancer cells rely on PIK3CA and are highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification confers PI3K dependence. Finally, genetic and pharmacological inhibition of PI3K suppresses PRR11-mediated, estrogen-independent growth. These data suggest ER+/PRR11-amplified breast cancers as a novel subgroup of tumors that may benefit from treatment with PI3K inhibitors and antiestrogens.
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Jeffreys SA, Powter B, Balakrishnar B, Mok K, Soon P, Franken A, Neubauer H, de Souza P, Becker TM. Endocrine Resistance in Breast Cancer: The Role of Estrogen Receptor Stability. Cells 2020; 9:cells9092077. [PMID: 32932819 PMCID: PMC7564140 DOI: 10.3390/cells9092077] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/06/2020] [Accepted: 09/08/2020] [Indexed: 12/13/2022] Open
Abstract
Therapy of hormone receptor positive breast cancer (BCa) generally targets estrogen receptor (ER) function and signaling by reducing estrogen production or by blocking its interaction with the ER. Despite good long-term responses, resistance to treatment remains a significant issue, with approximately 40% of BCa patients developing resistance to ET. Mutations in the gene encoding ERα, ESR1, have been identified in BCa patients and are implicated as drivers of resistance and disease recurrence. Understanding the molecular consequences of these mutations on ER protein levels and its activity, which is tightly regulated, is vital. ER activity is in part controlled via its short protein half-life and therefore changes to its stability, either through mutations or alterations in pathways involved in protein stability, may play a role in therapy resistance. Understanding these connections and how ESR1 alterations could affect protein stability may identify novel biomarkers of resistance. This review explores the current reported data regarding posttranslational modifications (PTMs) of the ER and the potential impact of known resistance associated ESR1 mutations on ER regulation by affecting these PTMs in the context of ET resistance.
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Affiliation(s)
- Sarah A. Jeffreys
- Centre for Circulating Tumour Cells Diagnostics & Research, Ingham Institute of Applied Medical Research, Liverpool NSW 2170, Australia; (B.P.); (P.S.); (A.F.); (P.d.S.); (T.M.B.)
- School of Medicine, Western Sydney University, Campbelltown NSW 2560, Australia
- Correspondence: ; Tel.: +61-2-873-89022
| | - Branka Powter
- Centre for Circulating Tumour Cells Diagnostics & Research, Ingham Institute of Applied Medical Research, Liverpool NSW 2170, Australia; (B.P.); (P.S.); (A.F.); (P.d.S.); (T.M.B.)
| | - Bavanthi Balakrishnar
- Department of Medical Oncology, Liverpool Hospital, Liverpool NSW 2170, Australia; (B.B.); (K.M.)
| | - Kelly Mok
- Department of Medical Oncology, Liverpool Hospital, Liverpool NSW 2170, Australia; (B.B.); (K.M.)
| | - Patsy Soon
- Centre for Circulating Tumour Cells Diagnostics & Research, Ingham Institute of Applied Medical Research, Liverpool NSW 2170, Australia; (B.P.); (P.S.); (A.F.); (P.d.S.); (T.M.B.)
- South Western Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool NSW 2170, Australia
- Department of Surgery, Bankstown Hospital, Bankstown NSW 2200, Australia
| | - André Franken
- Centre for Circulating Tumour Cells Diagnostics & Research, Ingham Institute of Applied Medical Research, Liverpool NSW 2170, Australia; (B.P.); (P.S.); (A.F.); (P.d.S.); (T.M.B.)
- Department of Obstetrics and Gynaecology, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany;
| | - Hans Neubauer
- Department of Obstetrics and Gynaecology, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany;
| | - Paul de Souza
- Centre for Circulating Tumour Cells Diagnostics & Research, Ingham Institute of Applied Medical Research, Liverpool NSW 2170, Australia; (B.P.); (P.S.); (A.F.); (P.d.S.); (T.M.B.)
- School of Medicine, Western Sydney University, Campbelltown NSW 2560, Australia
- Department of Medical Oncology, Liverpool Hospital, Liverpool NSW 2170, Australia; (B.B.); (K.M.)
- South Western Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool NSW 2170, Australia
- School of Medicine, University of Wollongong, Wollongong NSW 2522, Australia
| | - Therese M. Becker
- Centre for Circulating Tumour Cells Diagnostics & Research, Ingham Institute of Applied Medical Research, Liverpool NSW 2170, Australia; (B.P.); (P.S.); (A.F.); (P.d.S.); (T.M.B.)
- School of Medicine, Western Sydney University, Campbelltown NSW 2560, Australia
- South Western Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool NSW 2170, Australia
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Barchiesi G, Mazzotta M, Krasniqi E, Pizzuti L, Marinelli D, Capomolla E, Sergi D, Amodio A, Natoli C, Gamucci T, Vizza E, Marchetti P, Botti C, Sanguineti G, Ciliberto G, Barba M, Vici P. Neoadjuvant Endocrine Therapy in Breast Cancer: Current Knowledge and Future Perspectives. Int J Mol Sci 2020; 21:E3528. [PMID: 32429381 PMCID: PMC7278946 DOI: 10.3390/ijms21103528] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/07/2020] [Accepted: 05/14/2020] [Indexed: 12/12/2022] Open
Abstract
In locally advanced (LA) breast cancer (BC), neoadjuvant treatments have led to major achievements, which hold particular relevance in HER2-positive and triple-negative BC. Conversely, their role in hormone receptor positive (HR+), hormone epidermal growth factor 2 negative (HER2-) BC is still under debate, mainly due to the generally low rates of pathological complete response (pCR) and lower accuracy of pCR as predictors of long-term outcomes in this patient subset. While administration of neoadjuvant chemotherapy (NCT) in LA, HR+, HER2- BC patients is widely used in clinical practice, neoadjuvant endocrine therapy (NET) still retains an unfulfilled potential in the management of these subgroups, particularly in elderly and unfit patients. In addition, NET has gained a central role as a platform to test new drugs and predictive biomarkers in previously untreated patients. We herein present historical data regarding Tamoxifen and/or Aromatase Inhibitors and a debate on recent evidence regarding agents such as CDK4/6 and PI3K/mTOR inhibitors in the neoadjuvant setting. We also discuss key issues concerning the optimal treatment length, appropriate comparisons with NCT efficacy and use of NET in premenopausal patients.
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Affiliation(s)
| | - Marco Mazzotta
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (E.K.); (L.P.); (E.C.); (D.S.); (A.A.); (P.V.)
| | - Eriseld Krasniqi
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (E.K.); (L.P.); (E.C.); (D.S.); (A.A.); (P.V.)
| | - Laura Pizzuti
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (E.K.); (L.P.); (E.C.); (D.S.); (A.A.); (P.V.)
| | - Daniele Marinelli
- Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University; Medical Oncology Unit, 00189 Rome, Italy; (D.M.); (P.M.)
| | - Elisabetta Capomolla
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (E.K.); (L.P.); (E.C.); (D.S.); (A.A.); (P.V.)
| | - Domenico Sergi
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (E.K.); (L.P.); (E.C.); (D.S.); (A.A.); (P.V.)
| | - Antonella Amodio
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (E.K.); (L.P.); (E.C.); (D.S.); (A.A.); (P.V.)
| | - Clara Natoli
- Department of Medical, Oral & Biotechnological Sciences, University G. D’Annunzio, 66100 Chieti-Pescara, Italy;
| | - Teresa Gamucci
- Medical Oncology, Sandro Pertini Hospital, 00157 Rome, Italy;
| | - Enrico Vizza
- Department of Oncological Surgery, Gynecologic Oncologic Unit, “Regina Elena” National Cancer Institute, 00144 Rome, Italy;
| | - Paolo Marchetti
- Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University; Medical Oncology Unit, 00189 Rome, Italy; (D.M.); (P.M.)
- Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, 00161 Rome, Italy
| | - Claudio Botti
- Department of Surgery, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Giuseppe Sanguineti
- Department of Radiation Oncology, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Gennaro Ciliberto
- Scientific Direction, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Maddalena Barba
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (E.K.); (L.P.); (E.C.); (D.S.); (A.A.); (P.V.)
| | - Patrizia Vici
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (E.K.); (L.P.); (E.C.); (D.S.); (A.A.); (P.V.)
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Welt A, Wiesweg M, Theurer S, Abenhardt W, Groschek M, Müller L, Schröder J, Tewes M, Chiabudini M, Potthoff K, Bankfalvi A, Marschner N, Schuler M, Breitenbücher F. Buparlisib in combination with tamoxifen in pretreated patients with hormone receptor-positive, HER2-negative advanced breast cancer molecularly stratified for PIK3CA mutations and loss of PTEN expression. Cancer Med 2020; 9:4527-4539. [PMID: 32352244 PMCID: PMC7333856 DOI: 10.1002/cam4.3092] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/08/2020] [Indexed: 12/12/2022] Open
Abstract
The PIKTAM study evaluated the efficacy and safety of the PI3K inhibitor buparlisib in combination with tamoxifen in hormone receptor-positive (HR+ ), HER2-negative advanced breast cancer patients after failure of prior endocrine therapy. In this open-label, single-arm phase II trial, 25 patients were enrolled in 11 sites in Germany. Patients were stratified according to PIK3CA mutation status (tissue and cfDNA from serum samples) and/or loss of PTEN expression. Patients received buparlisib (100 mg) and tamoxifen (20 mg) once daily on a continuous schedule (28-day cycle) until progression or unacceptable toxicity. Primary endpoint was overall 6-month progression-free survival (PFS) rate. Key secondary endpoints included the 6-month PFS rate in subpopulations, PFS, overall survival, overall response rate (ORR), disease control rate (DCR), and safety. Overall, the 6-month PFS rate was 33.3% (n/N = 7/21, one-sided 95% CI 16.8-100) and median PFS was 6.1 (CI 2.6-10.6) months. The ORR and DCR were 12.5% and 44%. The PIK3CA-mutated subgroup consistently showed the highest 6-month PFS rate (62.5%, n/N = 5/8), median PFS (8.7 months), ORR (40%), and DCR (80%). No new safety signals emerged. Most common adverse events were gastrointestinal disorders (56%), psychiatric/mood disorders (48%), skin rash/hypersensitivity (44%), cardiovascular (40%), and hepatic (32%) events. The trial was prematurely terminated due to the substantially altered risk-benefit profile of buparlisib. Nevertheless, PIK3CA mutations emerged as a clinically feasible and useful biomarker for combined PI3K inhibition and endocrine therapy in patients with HR+ breast cancer. Further biomarker-stratified studies with isoform-specific PI3K inhibitors are warranted. EudraCT No: 2014-000599-24.
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Affiliation(s)
- Anja Welt
- Westdeutsches Tumorzentrum, Innere Klinik (Tumorforschung) Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | - Marcel Wiesweg
- Westdeutsches Tumorzentrum, Innere Klinik (Tumorforschung) Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | - Sarah Theurer
- Westdeutsches Tumorzentrum, Institut für Pathologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | | | | | - Lothar Müller
- Onkologie UnterEms Leer-Emden-Papenburg Annenstr. 11, Leer, Deutschland
| | - Jan Schröder
- Praxis für Hämatologie und Onkologie, Mülheim a.d.R, Deutschland
| | - Mitra Tewes
- Westdeutsches Tumorzentrum, Innere Klinik (Tumorforschung) Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | | | | | - Agnes Bankfalvi
- Westdeutsches Tumorzentrum, Institut für Pathologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | | | - Martin Schuler
- Westdeutsches Tumorzentrum, Innere Klinik (Tumorforschung) Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.,Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partnerstandort Universitätsklinikum Essen, Essen, Deutschland
| | - Frank Breitenbücher
- Westdeutsches Tumorzentrum, Innere Klinik (Tumorforschung) Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
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Hanker AB, Sudhan DR, Arteaga CL. Overcoming Endocrine Resistance in Breast Cancer. Cancer Cell 2020; 37:496-513. [PMID: 32289273 PMCID: PMC7169993 DOI: 10.1016/j.ccell.2020.03.009] [Citation(s) in RCA: 523] [Impact Index Per Article: 104.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/05/2020] [Accepted: 03/09/2020] [Indexed: 12/19/2022]
Abstract
Estrogen receptor-positive (ER+) breast cancer is the most common breast cancer subtype. Treatment of ER+ breast cancer comprises interventions that suppress estrogen production and/or target the ER directly (overall labeled as endocrine therapy). While endocrine therapy has considerably reduced recurrence and mortality from breast cancer, de novo and acquired resistance to this treatment remains a major challenge. An increasing number of mechanisms of endocrine resistance have been reported, including somatic alterations, epigenetic changes, and changes in the tumor microenvironment. Here, we review recent advances in delineating mechanisms of resistance to endocrine therapies and potential strategies to overcome such resistance.
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Affiliation(s)
- Ariella B Hanker
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - Dhivya R Sudhan
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Carlos L Arteaga
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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Li X, Lu J, Zhang L, Luo Y, Zhao Z, Li M. Clinical Implications of Monitoring ESR1 Mutations by Circulating Tumor DNA in Estrogen Receptor Positive Metastatic Breast Cancer: A Pilot Study. Transl Oncol 2020. [PMID: 31877464 DOI: 10.3760/cma.j.issn.1674-2397.2020.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND ESR1 mutations are frequently detected in ER+ MBC, and have been reported to be associated with endocrine therapy resistance. However, there are little researches to validate whether dynamic monitoring of ESR1 mutations could serve as a predictive plasma biomarker of acquired resistance to endocrine therapy. Therefore, in this study, we performed longitudinal circulating tumor DNA (ctDNA) detection to evaluate the clinical implications of monitoring ESR1 mutations. METHODS We performed longitudinal dynamic mutation analyses of plasma samples from 45 patients with metastatic breast cancer (MBC) and sequencing paired biopsy tissues, using a targeted NGS panel of 425 genes. These patients were treated at the Second Affiliated Hospital of Dalian Medical University between January 2017 and February 2019 with written informed consent. RESULTS Mutations profiles were highly concordant between plasma and paired tissue samples from 45 MBC patients (r = 0.96, P < 0.0001). ESR1 mutations were enriched in ER+ MBC patients after AI therapy (17.8%, 8/45). The median time from AI endocrine therapies to the initial detection of ESR1 mutation was 39 months (95% CI 21.32-57.57). Some hotspot mutations (Y537S (n = 5), Y537N (n = 1), D538G (n = 2), E380Q (n = 2)) and several rare mutations (L345SfsX7, 24fs, G344delinsGC) were identified in our cohort. In addition, we observed that two patients obtained multiple ESR1 mutations over the course of treatment (Y537N/Y537S/D538G, L345SfsX7/24fs/E380Q). Through dynamically monitoring ESR1 mutations by ctDNA, we demonstrated that the change of allele frequency of ESR1 mutations was an important biomarker, which could predict endocrine resistance of ER+ MBC in our study. We also observed that the combination of everolimus in four cases with acquired ESR1 mutations showed longer PFS than other therapies without everolimus. CONCLUSION The dynamic monitoring of ESR1 mutations by ctDNA is a promising tool to predict endocrine therapy resistance in ER+ MBC patients.
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Affiliation(s)
- Xuelu Li
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Jiawei Lu
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Lanxin Zhang
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Yaoting Luo
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Zuowei Zhao
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China.
| | - Man Li
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China.
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Li X, Lu J, Zhang L, Luo Y, Zhao Z, Li M. Clinical Implications of Monitoring ESR1 Mutations by Circulating Tumor DNA in Estrogen Receptor Positive Metastatic Breast Cancer: A Pilot Study. Transl Oncol 2020; 13:321-328. [PMID: 31877464 PMCID: PMC6931202 DOI: 10.1016/j.tranon.2019.11.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 11/10/2019] [Accepted: 11/12/2019] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND ESR1 mutations are frequently detected in ER+ MBC, and have been reported to be associated with endocrine therapy resistance. However, there are little researches to validate whether dynamic monitoring of ESR1 mutations could serve as a predictive plasma biomarker of acquired resistance to endocrine therapy. Therefore, in this study, we performed longitudinal circulating tumor DNA (ctDNA) detection to evaluate the clinical implications of monitoring ESR1 mutations. METHODS We performed longitudinal dynamic mutation analyses of plasma samples from 45 patients with metastatic breast cancer (MBC) and sequencing paired biopsy tissues, using a targeted NGS panel of 425 genes. These patients were treated at the Second Affiliated Hospital of Dalian Medical University between January 2017 and February 2019 with written informed consent. RESULTS Mutations profiles were highly concordant between plasma and paired tissue samples from 45 MBC patients (r = 0.96, P < 0.0001). ESR1 mutations were enriched in ER+ MBC patients after AI therapy (17.8%, 8/45). The median time from AI endocrine therapies to the initial detection of ESR1 mutation was 39 months (95% CI 21.32-57.57). Some hotspot mutations (Y537S (n = 5), Y537N (n = 1), D538G (n = 2), E380Q (n = 2)) and several rare mutations (L345SfsX7, 24fs, G344delinsGC) were identified in our cohort. In addition, we observed that two patients obtained multiple ESR1 mutations over the course of treatment (Y537N/Y537S/D538G, L345SfsX7/24fs/E380Q). Through dynamically monitoring ESR1 mutations by ctDNA, we demonstrated that the change of allele frequency of ESR1 mutations was an important biomarker, which could predict endocrine resistance of ER+ MBC in our study. We also observed that the combination of everolimus in four cases with acquired ESR1 mutations showed longer PFS than other therapies without everolimus. CONCLUSION The dynamic monitoring of ESR1 mutations by ctDNA is a promising tool to predict endocrine therapy resistance in ER+ MBC patients.
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Affiliation(s)
- Xuelu Li
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Jiawei Lu
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Lanxin Zhang
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Yaoting Luo
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Zuowei Zhao
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China.
| | - Man Li
- Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, 116023, China; Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China.
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Hosford SR, Shee K, Wells JD, Traphagen NA, Fields JL, Hampsch RA, Kettenbach AN, Demidenko E, Miller TW. Estrogen therapy induces an unfolded protein response to drive cell death in ER+ breast cancer. Mol Oncol 2019; 13:1778-1794. [PMID: 31180176 PMCID: PMC6670014 DOI: 10.1002/1878-0261.12528] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/19/2019] [Accepted: 06/07/2019] [Indexed: 01/06/2023] Open
Abstract
Estrogens have been shown to elicit anticancer effects against estrogen receptor α (ER)-positive breast cancer. We sought to determine the mechanism underlying the therapeutic response. Response to 17β-estradiol was assessed in ER+ breast cancer models with resistance to estrogen deprivation: WHIM16 patient-derived xenografts, C7-2-HI and C4-HI murine mammary adenocarcinomas, and long-term estrogen-deprived MCF-7 cells. As another means to reactivate ER, the anti-estrogen fulvestrant was withdrawn from fulvestrant-resistant MCF-7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17β-estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER, and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17β-estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anticancer effects were most pronounced in models exhibiting genomic amplification of the gene encoding ER (ESR1), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long-term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17β-estradiol treatment and anti-estrogen withdrawal hyperactivate ER, which drives an unfolded protein response and subsequent growth inhibition and apoptosis. 17β-estradiol treatment should be considered as a therapeutic option for anti-estrogen-resistant disease, particularly in patients with tumors harboring ESR1 amplification or ER overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may increase the therapeutic effects of ER reactivation.
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Affiliation(s)
- Sarah R Hosford
- Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Kevin Shee
- Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Jason D Wells
- Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Nicole A Traphagen
- Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Jennifer L Fields
- Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Riley A Hampsch
- Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Arminja N Kettenbach
- Department of Biochemistry, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Eugene Demidenko
- Department of Biomedical Data Sciences, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Todd W Miller
- Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.,Comprehensive Breast Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
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38
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Bacci M, Lorito N, Ippolito L, Ramazzotti M, Luti S, Romagnoli S, Parri M, Bianchini F, Cappellesso F, Virga F, Gao Q, Simões BM, Marangoni E, Martin LA, Comito G, Ferracin M, Giannoni E, Mazzone M, Chiarugi P, Morandi A. Reprogramming of Amino Acid Transporters to Support Aspartate and Glutamate Dependency Sustains Endocrine Resistance in Breast Cancer. Cell Rep 2019; 28:104-118.e8. [PMID: 31269432 PMCID: PMC6616584 DOI: 10.1016/j.celrep.2019.06.010] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 05/13/2019] [Accepted: 06/03/2019] [Indexed: 01/08/2023] Open
Abstract
Endocrine therapy (ET) is the standard of care for estrogen receptor-positive (ER+) breast cancers. Despite its efficacy, ∼40% of women relapse with ET-resistant (ETR) disease. A global transcription analysis in ETR cells reveals a downregulation of the neutral and basic amino acid transporter SLC6A14 governed by enhanced miR-23b-3p expression, resulting in impaired amino acid metabolism. This altered amino acid metabolism in ETR cells is supported by the activation of autophagy and the enhanced import of acidic amino acids (aspartate and glutamate) mediated by the SLC1A2 transporter. The clinical significance of these findings is validated by multiple orthogonal approaches in a large cohort of ET-treated patients, in patient-derived xenografts, and in in vivo experiments. Targeting these amino acid metabolic dependencies resensitizes ETR cells to therapy and impairs the aggressive features of ETR cells, offering predictive biomarkers and potential targetable pathways to be exploited to combat or delay ETR in ER+ breast cancers.
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Affiliation(s)
- Marina Bacci
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Nicla Lorito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Luigi Ippolito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Matteo Ramazzotti
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Simone Luti
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Simone Romagnoli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Matteo Parri
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Francesca Bianchini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Federica Cappellesso
- VIB Center for Cancer Biology, Department of Oncology, University of Leuven, Leuven 3000, Belgium
| | - Federico Virga
- VIB Center for Cancer Biology, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin 10126, Italy
| | - Qiong Gao
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
| | - Bruno M Simões
- Breast Cancer Now Research Unit, Division of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester M20 4GJ, UK
| | - Elisabetta Marangoni
- Institut Curie, PSL Research University, Translational Research Department, Paris 75248, France
| | - Lesley-Ann Martin
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
| | - Giuseppina Comito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Manuela Ferracin
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna 40126, Italy
| | - Elisa Giannoni
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Massimiliano Mazzone
- VIB Center for Cancer Biology, Department of Oncology, University of Leuven, Leuven 3000, Belgium
| | - Paola Chiarugi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Andrea Morandi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy.
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39
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Poulard C, Jacquemetton J, Trédan O, Cohen PA, Vendrell J, Ghayad SE, Treilleux I, Marangoni E, Le Romancer M. Oestrogen Non-Genomic Signalling is Activated in Tamoxifen-Resistant Breast Cancer. Int J Mol Sci 2019; 20:ijms20112773. [PMID: 31195751 PMCID: PMC6600329 DOI: 10.3390/ijms20112773] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/31/2019] [Accepted: 05/31/2019] [Indexed: 01/03/2023] Open
Abstract
Endocrine therapies targeting oestrogen signalling have significantly improved breast cancer management. However, their efficacy is limited by intrinsic and acquired resistance to treatment, which remains a major challenge for oestrogen receptor α (ERα)-positive tumours. Though many studies using in vitro models of endocrine resistance have identified putative actors of resistance, no consensus has been reached. We demonstrated previously that oestrogen non-genomic signalling, characterized by the formation of the ERα/Src/PI3K complex, is activated in aggressive breast cancers (BC). We wondered herein whether the activation of this pathway is also involved in resistance to endocrine therapies. We studied the interactions between ERα and Src or PI3K by proximity ligation assay (PLA) in in-vitro and in-vivo endocrine therapy-resistant breast cancer models. We reveal an increase in ERα/Src and ERα/PI3K interactions in patient-derived xenografts (PDXs) with acquired resistance to tamoxifen, as well as in tamoxifen-resistant MCF-7 cells compared to parental counterparts. Moreover, no interactions were observed in breast cancer cells resistant to other endocrine therapies. Finally, the use of a peptide inhibiting the ERα–Src interaction partially restored tamoxifen sensitivity in resistant cells, suggesting that such components could constitute promising targets to circumvent resistance to tamoxifen in BC.
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Affiliation(s)
- Coralie Poulard
- Université de Lyon, F-69000 Lyon, France.
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
| | - Julien Jacquemetton
- Université de Lyon, F-69000 Lyon, France.
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
| | - Olivier Trédan
- Université de Lyon, F-69000 Lyon, France.
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- Centre Léon Bérard, Medical Oncology Department, F-69000 Lyon, France.
| | - Pascale A Cohen
- Université de Lyon, F-69000 Lyon, France.
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
| | - Julie Vendrell
- Université de Lyon, F-69000 Lyon, France.
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- Solid Tumor Laboratory, Department of Pathology and Oncobiology, CHU Montpellier, 34000 Montpellier, France.
| | - Sandra E Ghayad
- Université de Lyon, F-69000 Lyon, France.
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- Department of Biology, Faculty of Science II, EDST, Lebanese University, Fanar 90656, Lebanon.
| | - Isabelle Treilleux
- Université de Lyon, F-69000 Lyon, France.
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- Centre Léon Bérard, Pathology Department, F-69000 Lyon, France.
| | | | - Muriel Le Romancer
- Université de Lyon, F-69000 Lyon, France.
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
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Sabbah DA, Ibrahim AH, Talib WH, Alqaisi KM, Sweidan K, Bardaweel SK, Sheikha GA, Zhong HA, Al-Shalabi E, Khalaf RA, Mubarak MS. Ligand-Based Drug Design: Synthesis and Biological Evaluation of Substituted Benzoin Derivatives as Potential Antitumor Agents. Med Chem 2019; 15:417-429. [DOI: 10.2174/1573406414666180912111846] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 09/02/2018] [Accepted: 09/10/2018] [Indexed: 11/22/2022]
Abstract
Background:
Phosphoinositide 3-kinase α (PI3Kα) has emerged as a promising target
for anticancer drug design.
Objectives:
Target compounds were designed to investigate the effect of the p-OCH3 motifs on
ligand/PI3Kα complex interaction and antiproliferative activity.
Methods:
Synthesis of the proposed compounds, biological examination tests against human colon
adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell
lines, along with Glide docking studies.
Results:
A series of 1,2-bis(4-methoxyphenyl)-2-oxoethyl benzoates was synthesized and characterized
by means of FT-IR, 1H and 13C NMR, and by elemental analysis. Biological investigation
demonstrated that the newly synthesized compounds exhibit antiproliferative activity in human colon
adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D)
cell lines possibly via inhibition of PI3Kα and estrogen receptor alpha (ERα). Additionally, results
revealed that these compounds exert selective inhibitory activity, induce apoptosis, and suppress
VEGF production. Compound 3c exhibited promising antiproliferative activity in HCT-116 interrogating
that hydrogen bond-acceptor mediates ligand/PI3Kα complex formation on m- position.
Compounds 3e and 3i displayed high inhibitory activity in MCF-7 and T47D implying a wide cleft
discloses the o-attachment. Furthermore, compound 3g exerted selective inhibitory activity against
T47D. Glide docking studies against PI3Kα and ERα demonstrated that the series accommodate
binding to PI3Kα and/or ERα.
Conclusion:
The series exhibited a potential antitumor activity in human carcinoma cell lines encoding
PI3Kα and/or ERα.
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Affiliation(s)
- Dima A. Sabbah
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733, Jordan
| | - Ameerah H. Ibrahim
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733, Jordan
| | - Wamidh H. Talib
- Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Amman, Jordan
| | - Khalid M. Alqaisi
- Department of Allied Medical Sciences, Zarqa University College, Al-Balqa Applied University, P.O. Box 132222, Zarqa 13132, Jordan
| | - Kamal Sweidan
- Department of Chemistry, The University of Jordan, Amman 11942, Jordan
| | - Sanaa K. Bardaweel
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan
| | - Ghassan A. Sheikha
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733, Jordan
| | - Haizhen A. Zhong
- DSC 362, Department of Chemistry, The University of Nebraska at Omaha, 6001 Dodge Street, Omaha, Nebraska 68182, United States
| | - Eveen Al-Shalabi
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733, Jordan
| | - Reema A. Khalaf
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733, Jordan
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Mayer IA, Prat A, Egle D, Blau S, Fidalgo JAP, Gnant M, Fasching PA, Colleoni M, Wolff AC, Winer EP, Singer CF, Hurvitz S, Estévez LG, van Dam PA, Kümmel S, Mundhenke C, Holmes F, Babbar N, Charbonnier L, Diaz-Padilla I, Vogl FD, Sellami D, Arteaga CL. A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB). Clin Cancer Res 2019; 25:2975-2987. [PMID: 30723140 PMCID: PMC6522303 DOI: 10.1158/1078-0432.ccr-18-3160] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/20/2018] [Accepted: 01/23/2019] [Indexed: 12/13/2022]
Abstract
PURPOSE Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor-positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting.Patients and Methods: Postmenopausal women with HR+, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. RESULTS In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole. CONCLUSIONS In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR+ early breast cancer.
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Affiliation(s)
- Ingrid A Mayer
- Department of Medicine, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
| | - Aleix Prat
- Translational Genomics and Targeted Therapeutics in Solid Tumors, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Daniel Egle
- Department of Gynecology and Obstetrics, Medical University of Innsbruck, Innsbruck, Austria
| | - Sibel Blau
- Rainier Hematology-Oncology, Northwest Medical Specialties, Tacoma, Washington
| | - J Alejandro Pérez Fidalgo
- Department of Oncology, CIBERONC, Hospital Clínico Universitario de Valencia - INCLIVA, Valencia, Spain
| | - Michael Gnant
- Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Peter A Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen and Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Erlangen, Germany
| | - Marco Colleoni
- Division of Medical Senology, European Institute of Oncology (IEO), IRCCS, Milan, and International Breast Cancer Study Group, Milan, Italy
| | - Antonio C Wolff
- Department of Oncology, The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Eric P Winer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Christian F Singer
- Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Sara Hurvitz
- Department of Medicine, University of California, Los Angeles, California
| | | | - Peter A van Dam
- Gynecologic Oncology and Senology, Antwerp University Hospital, Edegem, Belgium
| | | | - Christoph Mundhenke
- Department of Obstetrics and Gynecology, Universitätsklinikum Schleswig-Holstein, Kiel, Germany
| | - Frankie Holmes
- Texas Oncology-Houston Memorial City and US Oncology Research Network, Houston, Texas
| | - Naveen Babbar
- Oncology Precision Medicine, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey
| | | | | | - Florian D Vogl
- Oncology Global Development, Novartis Pharma AG, Basel, Switzerland
| | - Dalila Sellami
- Oncology Precision Medicine, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey
| | - Carlos L Arteaga
- Department of Medicine, UTSW Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas.
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Lei JT, Gou X, Seker S, Ellis MJ. ESR1 alterations and metastasis in estrogen receptor positive breast cancer. ACTA ACUST UNITED AC 2019; 5. [PMID: 31106278 PMCID: PMC6519472 DOI: 10.20517/2394-4722.2019.12] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Endocrine therapy is essential for the treatment of patients with estrogen receptor positive (ER+) breast cancer, however, resistance and the development of metastatic disease is common. Understanding how ER+ breast cancer metastasizes is critical since the major cause of death in breast cancer is metastasis to distant organs. Results from many studies suggest dysregulation of the estrogen receptor alpha gene (ESR1 ) contributes to therapeutic resistance and metastatic biology. This review covers both pre-clinical and clinical evidence on the spectrum of ESR1 alterations including amplification, point mutations, and genomic rearrangement events driving treatment resistance and metastatic potential of ER+ breast cancer. Importantly, we describe how these ESR1 alterations may provide therapeutic opportunities to improve outcomes in patients with lethal, metastatic breast cancer.
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Affiliation(s)
- Jonathan T Lei
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xuxu Gou
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sinem Seker
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Matthew J Ellis
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.,Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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43
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Sammons S, Kornblum NS, Blackwell KL. Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer. Target Oncol 2019; 14:1-12. [PMID: 30136059 PMCID: PMC6407749 DOI: 10.1007/s11523-018-0587-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Fulvestrant is recommended for patients with hormone receptor-positive (HR+) advanced breast cancer (ABC) who progress after aromatase inhibitor therapy. As most patients in this setting have already developed mechanisms of resistance to endocrine therapy, targeting biological pathways associated with endocrine resistance in combination with fulvestrant may improve outcomes. Therefore, evidence supporting a combinatorial treatment approach in the second-line setting was investigated based on a search of PubMed and ClinicalTrials.gov . Twenty-eight studies of targeted therapies plus fulvestrant as second-line treatment for HR+ ABC were identified, including three and six key randomized trials exploring cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors plus fulvestrant respectively. Additional combinations with fulvestrant included inhibitors of epidermal growth factor receptors, androgen receptor, and the bromodomain and extra-terminal family of proteins. Across the studies reviewed with available data, the addition of targeted therapies to fulvestrant resulted in clinically meaningful improvements in progression-free survival compared with fulvestrant alone. While some challenging toxicities were observed, most adverse events could be effectively managed. Selection of second-line targeted therapy for use with fulvestrant should consider prior treatment as well as the mutation status of the tumor. In conclusion, available data indicate that fulvestrant combined with agents targeting mechanisms of endocrine resistance is a promising approach. The ongoing trials identified in this review will help further inform the selection of combination treatments with fulvestrant for HR+ ABC.
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Affiliation(s)
| | | | - Kimberly L. Blackwell
- Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA
- Present Address: Eli Lilly and Company, Indianapolis, IN 46285 USA
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44
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Stratikopoulos EE, Kiess N, Szabolcs M, Pegno S, Kakit C, Wu X, Poulikakos PI, Cheung P, Schmidt H, Parsons R. Mouse ER+/PIK3CA H1047R breast cancers caused by exogenous estrogen are heterogeneously dependent on estrogen and undergo BIM-dependent apoptosis with BH3 and PI3K agents. Oncogene 2019; 38:47-59. [PMID: 30076411 PMCID: PMC6596308 DOI: 10.1038/s41388-018-0436-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 07/09/2018] [Accepted: 07/14/2018] [Indexed: 01/03/2023]
Abstract
Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.
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MESH Headings
- Aniline Compounds/administration & dosage
- Aniline Compounds/pharmacology
- Animals
- Antineoplastic Agents, Hormonal/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Apoptosis/drug effects
- Apoptosis Regulatory Proteins/antagonists & inhibitors
- BH3 Interacting Domain Death Agonist Protein/antagonists & inhibitors
- Bcl-2-Like Protein 11/agonists
- Bcl-2-Like Protein 11/biosynthesis
- Bcl-2-Like Protein 11/genetics
- Bcl-2-Like Protein 11/physiology
- Cell Line, Tumor
- Class I Phosphatidylinositol 3-Kinases
- Cocarcinogenesis
- Drug Resistance, Neoplasm
- Drug Screening Assays, Antitumor
- Drug Synergism
- Estradiol/toxicity
- Estrogen Receptor alpha/drug effects
- Estrogen Receptor alpha/physiology
- Female
- Fulvestrant/administration & dosage
- Fulvestrant/pharmacology
- Gene Expression Regulation, Neoplastic/drug effects
- Gene Knock-In Techniques
- Mammary Neoplasms, Experimental/chemically induced
- Mammary Neoplasms, Experimental/drug therapy
- Mammary Neoplasms, Experimental/genetics
- Mammary Neoplasms, Experimental/pathology
- Mice
- Mice, Nude
- Mutation, Missense
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/genetics
- Neoplasm Proteins/physiology
- Neoplasms, Hormone-Dependent/chemically induced
- Neoplasms, Hormone-Dependent/drug therapy
- Neoplasms, Hormone-Dependent/genetics
- Neoplasms, Hormone-Dependent/pathology
- Neuropeptides/antagonists & inhibitors
- Phosphatidylinositol 3-Kinases/genetics
- Phosphatidylinositol 3-Kinases/physiology
- Phosphoinositide-3 Kinase Inhibitors
- Sulfonamides/administration & dosage
- Sulfonamides/pharmacology
- Thiazoles/administration & dosage
- Thiazoles/pharmacology
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Affiliation(s)
- Elias E Stratikopoulos
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Nicole Kiess
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Matthias Szabolcs
- Department of Pathology, Columbia University Medical Center, New York, NY, 10032, USA
| | - Sarah Pegno
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Cheung Kakit
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Xuewei Wu
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Poulikos I Poulikakos
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Pamela Cheung
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Hank Schmidt
- Department of Surgery, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ramon Parsons
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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Al-Blewi FF, Rezki N, Al-Sodies SA, Bardaweel SK, Sabbah DA, Messali M, Aouad MR. Novel amphiphilic pyridinium ionic liquids-supported Schiff bases: ultrasound assisted synthesis, molecular docking and anticancer evaluation. Chem Cent J 2018; 12:118. [PMID: 30467608 PMCID: PMC6768046 DOI: 10.1186/s13065-018-0489-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 11/13/2018] [Indexed: 11/15/2022] Open
Abstract
Background Pyridinium Schiff bases and ionic liquids have attracted increasing interest in medicinal chemistry. Results A library of 32 cationic fluorinated pyridinium hydrazone-based amphiphiles tethering fluorinated counteranions was synthesized by alkylation of 4-fluoropyridine hydrazone with various long alkyl iodide exploiting lead quaternization and metathesis strategies. All compounds were assessed for their anticancer inhibition activity towards different cancer cell lines and the results revealed that increasing the length of the hydrophobic chain of the synthesized analogues appears to significantly enhance their anticancer activities. Substantial increase in caspase-3 activity was demonstrated upon treatment with the most potent compounds, namely 8, 28, 29 and 32 suggesting an apoptotic cellular death pathway. Conclusions Quantum-polarized ligand docking studies against phosphoinositide 3-kinase α displayed that compounds 2–6 bind to the kinase site and form H-bond with S774, K802, H917 and D933. ![]() Electronic supplementary material The online version of this article (10.1186/s13065-018-0489-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fawzia Faleh Al-Blewi
- Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah, Medina, 30002, Saudi Arabia
| | - Nadjet Rezki
- Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah, Medina, 30002, Saudi Arabia. .,Department of Chemistry, Faculty of Sciences, University of Sciences and Technology Mohamed Boudiaf, Laboratoire de Chimie et Electrochimie des Complexes Metalliques (LCECM) USTO-MB, P.O. Box 1505, El M'nouar, 31000, Oran, Algeria.
| | - Salsabeel Abdullah Al-Sodies
- Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah, Medina, 30002, Saudi Arabia
| | - Sanaa K Bardaweel
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman, 11942, Jordan
| | - Dima A Sabbah
- Faculty of Pharmacy, Al-Zaytoonah University, Amman, 11733, Jordan
| | - Mouslim Messali
- Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah, Medina, 30002, Saudi Arabia
| | - Mohamed Reda Aouad
- Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah, Medina, 30002, Saudi Arabia.
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46
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Liang X, Briaux A, Becette V, Benoist C, Boulai A, Chemlali W, Schnitzler A, Baulande S, Rivera S, Mouret-Reynier MA, Bouvet LV, De La Motte Rouge T, Lemonnier J, Lerebours F, Callens C. Molecular profiling of hormone receptor-positive, HER2-negative breast cancers from patients treated with neoadjuvant endocrine therapy in the CARMINA 02 trial (UCBG-0609). J Hematol Oncol 2018; 11:124. [PMID: 30305115 PMCID: PMC6180434 DOI: 10.1186/s13045-018-0670-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 09/26/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Postmenopausal women with large, hormone receptor (HR)-positive/HER2-negative and low-proliferative breast cancer derived a benefit from neoadjuvant endocrine therapy (NET) in the CARMINA02 trial. This study was designed to correlate gene expression and mutation profiles with both response to NET and prognosis. METHODS Gene expression profiling using RNA sequencing was performed in 86 pre-NET and post-NET tumor samples. Targeted next-generation sequencing of 91 candidate breast cancer-associated genes was performed on DNA samples from 89 patients. Molecular data were correlated with radiological response and relapse-free survival. RESULTS The transcriptional profile of tumors to NET in responders involved immune-associated genes enriched in activated Th1 pathway, which remained unchanged in non-responders. Immune response was confirmed by analysis of tumor-infiltrating lymphocytes (TILs). The percentage of TILs was significantly increased post-NET compared to pre-NET samples in responders (p = 0.0071), but not in non-responders (p = 0.0938). Gene expression revealed that lipid metabolism was the main molecular function related to prognosis, while PPARγ is the most important upstream regulator gene. The most frequently mutated genes were PIK3CA (48.3%), CDH1 (20.2%), PTEN (15.7%), TP53 (10.1%), LAMA2 (10.1%), BRCA2 (9.0%), MAP3K1 (7.9%), ALK (6.7%), INPP4B (6.7%), NCOR1 (6.7%), and NF1 (5.6%). Cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway were altered significantly more frequently in non-responders than in responders (p = 0.0017 and p = 0.0094, respectively). The average number of mutations per sample was significantly higher in endocrine-resistant tumors (2.88 vs. 1.64, p = 0.03), but no difference was observed in terms of prognosis. ESR1 hotspot mutations were detected in 3.4% of treatment-naive tumors. CONCLUSIONS The Th1-related immune system and lipid metabolism appear to play key roles in the response to endocrine therapy and prognosis in HR-positive/HER2-negative breast cancer. Deleterious somatic mutations in the cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway may be relevant for clinical management. TRIAL REGISTRATION This trial is registered with ClinicalTrials.gov ( NCT00629616 ) on March 6, 2008, retrospectively registered.
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Affiliation(s)
- Xu Liang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China.,Pharmacogenomic Unit, Department of Genetics, Curie Institute, PSL Research University, Paris, France
| | - Adrien Briaux
- Pharmacogenomic Unit, Department of Genetics, Curie Institute, PSL Research University, Paris, France
| | - Véronique Becette
- Department of Biopathology, Curie Institute, René Huguenin Hospital, Saint-Cloud, France
| | - Camille Benoist
- Pharmacogenomic Unit, Department of Genetics, Curie Institute, PSL Research University, Paris, France
| | - Anais Boulai
- Pharmacogenomic Unit, Department of Genetics, Curie Institute, PSL Research University, Paris, France
| | - Walid Chemlali
- Pharmacogenomic Unit, Department of Genetics, Curie Institute, PSL Research University, Paris, France
| | - Anne Schnitzler
- Pharmacogenomic Unit, Department of Genetics, Curie Institute, PSL Research University, Paris, France
| | - Sylvain Baulande
- Institut Curie Genomics of Excellence (ICGex) Platform, Curie Institute, PSL Research University, Paris, France
| | - Sofia Rivera
- Department of Radiotherapy, Gustave Roussy, Villejuif, France
| | | | | | | | | | - Florence Lerebours
- Department of Medical Oncology, Curie Institute, René Huguenin Hospital, Saint-Cloud, France
| | - Céline Callens
- Pharmacogenomic Unit, Department of Genetics, Curie Institute, PSL Research University, Paris, France.
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47
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Campone M, Im SA, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiełło-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Cortés J, De Laurentiis M, Arteaga CL, Jiang Z, Jonat W, Le Mouhaër S, Sankaran B, Bourdeau L, El-Hashimy M, Sellami D, Baselga J. Buparlisib plus fulvestrant versus placebo plus fulvestrant for postmenopausal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer: Overall survival results from BELLE-2. Eur J Cancer 2018; 103:147-154. [PMID: 30241001 DOI: 10.1016/j.ejca.2018.08.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 08/06/2018] [Accepted: 08/09/2018] [Indexed: 11/18/2022]
Abstract
BACKGROUND Buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus fulvestrant in the BELLE-2 study significantly improved progression-free survival (PFS) in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. PATIENTS AND METHODS In this phase III study, patients were randomised 1:1 to buparlisib (100 mg/day; continuously in 28-day cycles) or placebo, plus fulvestrant (500 mg on cycle 1 day 15, and day 1 of subsequent cycles). Overall survival (OS) was assessed in the overall population and patients with known PI3K pathway status (both had shown significant PFS improvements). OS by PIK3CA status in circulating tumour DNA (ctDNA) was an exploratory end-point. RESULTS A total of 2025 patients were screened for eligibility between 7th September 2012 and 10th September 2014, and 1178 received fulvestrant (500 mg) during a run-in phase; 31 discontinued. Of 1147 patients (median age 62 years), 98% had the Eastern Cooperative Oncology Group performance status ≤1, and 59% had visceral disease. Median follow-up from randomisation to data cut-off (23rd December 2016) was 37.6 months. Median OS trended in favour of the buparlisib arm in the overall population (33.2 versus 30.4 months; P = 0.045) and among patients with known PI3K pathway status (30.9 versus 28.9 months; P = 0.144); neither outcome was statistically significant. Median OS also trended in favour of buparlisib among patients with PIK3CA-mutant ctDNA (26.0 versus 24.8 months). Grade III/IV adverse events with ≥10% difference between the buparlisib versus placebo arms were elevated alanine aminotransferase (26% versus 1%), elevated aspartate aminotransferase (18% versus 3%) and hyperglycemia (15% versus <1%). CONCLUSIONS OS results were in favour of buparlisib plus fulvestrant versus placebo plus fulvestrant; however, there is no statistical significance and more frequent grade III/IV adverse events were reported. Use of more selective PI3K inhibitors might provide the greatest clinical benefit and tolerable safety profile in this setting. Further evaluation of the predictive benefit of PIK3CA-mutant ctDNA is warranted. TRIAL REGISTRATION NUMBER NCT01610284.
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Affiliation(s)
- Mario Campone
- Centre René Gauducheau, Institut de Cancérologie de L'Ouest, Saint Herblain, France.
| | - Seock-Ah Im
- Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hiroji Iwata
- Department of Breast Oncology, Aichi Cancer Center, Nagoya, Japan
| | - Mark Clemons
- Division of Medical Oncology, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Yoshinori Ito
- Breast Oncology Center, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Ahmad Awada
- Medical Oncology Clinic, Institut Jules Bordet, Brussels, Belgium
| | - Stephen Chia
- Medical Oncology, BC Cancer Agency, Vancouver, Canada
| | - Agnieszka Jagiełło-Gruszfeld
- Oncology Center, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology (MCMCC), Warsaw, Poland
| | | | - Ling-Ming Tseng
- Department of Surgery, Taipei-Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan
| | - Sara Hurvitz
- UCLA Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, USA
| | - Norikazu Masuda
- Department of Surgery and Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Javier Cortés
- Institute of Oncology, Ramón y Cajal University Hospital, Madrid, Spain; Breast Cancer Research Program, Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Michele De Laurentiis
- Breast Cancer Department, Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy
| | - Carlos L Arteaga
- Vanderbilt-Ingram Cancer Center, Department of Medicine, Vanderbilt University, Nashville, USA
| | - Zefei Jiang
- Department of Breast Cancer, Beijing 307 Hospital of PLA, Beijing, China
| | - Walter Jonat
- Medical Center, University Hospital Schleswig-Holstein, Kiel, Germany
| | | | - Banu Sankaran
- Novartis Institutes for BioMedical Research, Cambridge, USA
| | | | | | | | - José Baselga
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
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48
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Siersbæk R, Kumar S, Carroll JS. Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer. Genes Dev 2018; 32:1141-1154. [PMID: 30181360 PMCID: PMC6120708 DOI: 10.1101/gad.316646.118] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Estrogen receptor α (ER) is the major driver of ∼75% of breast cancers, and multiple ER targeting drugs are routinely used clinically to treat patients with ER+ breast cancer. However, many patients relapse on these targeted therapies and ultimately develop metastatic and incurable disease, and understanding the mechanisms leading to drug resistance is consequently of utmost importance. It is now clear that, in addition to estrogens, ER function is modulated by other steroid receptors and multiple signaling pathways (e.g., growth factor and cytokine signaling), and many of these pathways affect drug resistance and patient outcome. Here, we review the mechanisms through which these pathways impact ER function and drug resistance as well as discuss the clinical implications.
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Affiliation(s)
- Rasmus Siersbæk
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - Sanjeev Kumar
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Addenbrookes Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Jason S Carroll
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
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49
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Rezki N, Messali M, Al-Sodies SA, Naqvi A, Bardaweel SK, Al-blewi FF, Aouad MR, El Ashry ESH. Design, synthesis, in-silico and in-vitro evaluation of di-cationic pyridinium ionic liquids as potential anticancer scaffolds. J Mol Liq 2018. [DOI: 10.1016/j.molliq.2018.06.045] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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50
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Kaymak A, Sayols S, Papadopoulou T, Richly H. Role for the transcriptional activator ZRF1 in early metastatic events in breast cancer progression and endocrine resistance. Oncotarget 2018; 9:28666-28690. [PMID: 29983888 DOI: 10.18632/oncotarget.25596] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 05/24/2018] [Indexed: 02/07/2023] Open
Abstract
Breast cancer is one of the most common malignancies among women which is often treated with hormone therapy and chemotherapy. Despite the improvements in detection and treatment of breast cancer, the vast majority of breast cancer patients are diagnosed with metastatic disease either at the beginning of the disease or later during treatment. Still, the molecular mechanisms causing a therapy resistant metastatic breast cancer are still elusive. In the present study we addressed the function of the transcriptional activator ZRF1 during breast cancer progression. We provide evidence that ZRF1 plays an essential role for the early metastatic events in vitro and acts like a tumor suppressor protein during the progression of breast invasive ductal carcinoma into a more advanced stage. Hence, depletion of ZRF1 results in the acquisition of metastatic behavior by facilitating the initiation of the metastatic cascade, notably for cell adhesion, migration and invasion. Furthermore absence of ZRF1 provokes endocrine resistance via misregulation of cell death and cell survival related pathways. Taken together, we have identified ZRF1 as an important regulator of breast cancer progression that holds the potential to be explored for new treatment strategies in the future.
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Affiliation(s)
- Aysegül Kaymak
- Laboratory of Molecular Epigenetics, Institute of Molecular Biology, Mainz, Germany
| | - Sergi Sayols
- Bioinformatics Core Facility, Institute of Molecular Biology, Mainz, Germany
| | - Thaleia Papadopoulou
- Laboratory of Molecular Epigenetics, Institute of Molecular Biology, Mainz, Germany.,Department of Developmental and Stem Cell Biology, Institute Pasteur, Paris, France
| | - Holger Richly
- Laboratory of Molecular Epigenetics, Institute of Molecular Biology, Mainz, Germany
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