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Luo L, Yuan F, Palovcak A, Li F, Yuan Q, Calkins D, Manalo Z, Li Y, Wang D, Zhou M, Zhou C, Li M, Tan YD, Bai F, Ban Y, Mason C, Roberts E, Bilbao D, Liu ZJ, Briegel K, Welford SM, Pei XH, Daunert S, Liu W, Zhang Y. Oncogenic properties of wild-type DNA repair gene FANCA in breast cancer. Cell Rep 2025; 44:115480. [PMID: 40146775 DOI: 10.1016/j.celrep.2025.115480] [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: 09/23/2024] [Revised: 01/10/2025] [Accepted: 03/07/2025] [Indexed: 03/29/2025] Open
Abstract
FANCA is one of the 23 genes whose deficiencies lead to defective DNA interstrand crosslink repair and cancer-prone Fanconi anemia disease. Beyond its functions in DNA repair and tumor suppression, we report that high FANCA expression is strongly associated with breast cancer development. Overexpression of WT-FANCA significantly promotes breast cancer cell proliferation and tumor growth both in vitro and in vivo, while FANCA deficiency severely compromises the proliferation of breast cancer cells, but not non-tumorigenic breast epithelial cells. Heterozygous knockout of FANCA in breast cancer mouse models is sufficient to cause significant reduction of breast tumor growth in vivo. Furthermore, we have shown that high FANCA expression in breast cancer correlates with promoter hypomethylation in a TET-dependent manner, and TET inhibition recapitulates the proliferation defects caused by FANCA deficiency. Our study identifies the oncogenic properties of WT-FANCA and shows that FANCA is a promising target for breast cancer intervention.
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Affiliation(s)
- Liang Luo
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Fenghua Yuan
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Anna Palovcak
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Fang Li
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Qingqi Yuan
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Daniel Calkins
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Zoe Manalo
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Yan Li
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Dazhi Wang
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Mike Zhou
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Catherine Zhou
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Matthew Li
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Yuan-De Tan
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Feng Bai
- International Cancer Center, Shenzhen University Medical School, Shenzhen 518060, China
| | - Yuguang Ban
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Christian Mason
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Evan Roberts
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Daniel Bilbao
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Pathology & Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Zhao-Jun Liu
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Karoline Briegel
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Scott M Welford
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Xin-Hai Pei
- International Cancer Center, Shenzhen University Medical School, Shenzhen 518060, China
| | - Sylvia Daunert
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Wenjun Liu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, China.
| | - Yanbin Zhang
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
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Wang S, Luo X. A First-Principles Study of Graphene and Graphene Oxide as Potential Tamoxifen Drug Delivery Vehicles for Breast Cancer. ACS OMEGA 2025; 10:5593-5600. [PMID: 39989753 PMCID: PMC11840592 DOI: 10.1021/acsomega.4c08517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 01/19/2025] [Accepted: 01/22/2025] [Indexed: 02/25/2025]
Abstract
Targeted therapy with tamoxifen is an effective method to treat breast cancer. This method requires competent drug delivery vehicles to ensure successful therapeutic practices. The stable adsorption between the drug and delivery vehicle is one of the essential components. Using first-principles calculations, the adsorption behaviors of tamoxifen on reduced graphene and graphene oxide were studied based on density functional theory. The results indicated that tamoxifen was weakly adsorbed on pristine graphene, while it was relatively strongly adsorbed on reduced graphene oxides. Our results concluded that among the systems of reduced graphene oxide with an oxygen concentration of 0%, 3.125%, and 12.5%, graphene sheets with oxygen were potential candidates for tamoxifen delivery vehicles for breast cancer targeted therapy, and graphene oxide with an oxygen concentration of 12.5% was the most promising one compared to other carbon-based vehicles.
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Affiliation(s)
- Suri Wang
- National Graphene Research
and Development Center, Springfield, Virginia 22151, United States
| | - Xuan Luo
- National Graphene Research
and Development Center, Springfield, Virginia 22151, United States
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Rahaman W, Chaudhuri A. Self-assembled Lipid Nanoparticles for Killing Triple Negative Breast Cancer Cells. Chem Asian J 2025; 20:e202401049. [PMID: 39466002 DOI: 10.1002/asia.202401049] [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: 08/22/2024] [Revised: 10/08/2024] [Accepted: 10/22/2024] [Indexed: 10/29/2024]
Abstract
Triple negative breast cancers (TNBCs) lacking estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) on their cell surfaces are highly aggressive, difficult-to-treat and often relapse. Herein, we report on the self-assembled lipid nanoparticles (LNPs) of two new pegylated lipopeptides for killing TNBCs (MDA-MB-231). The pegylated lipopeptides were synthesized by conjugating an n-hexadecyl hydrophobic tail to one end of a (PEG)27 unit the other distal end of which was covalently grafted with two previously reported tumor targeting RGDK- and CGKRK- peptides. The SEM images of the self-assembled LNPs formed upon dissolution of the pegylated lipopeptides in aqueous medium revealed formation of spherical aggregates. The degree of cellular uptake for the self-assembled LNPs formed by the pegylated CGKRK-lipopeptide were found to be significantly higher than that for the self-assembled LNPs formed by the pegylated RGDK-lipopeptide in MCF-7, MDA-MB-231, HEK-293 and HFF cells. Notably, about 60 % TNBCs (MDA-MB-231 cells) were killed upon treatment with commercially available potent JAK2 inhibitor (WP 1066) loaded LNPs of the pegylated RGDK-lipopeptide. Contrastingly, the same treatment killed only about 20 % non-cancerous HEK-293 cells. The self-assembled pegylated LNPs described herein open the door for undertaking preclinical studies in animal models for TNBCs.
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Affiliation(s)
- Wahida Rahaman
- Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, West Bengal, 741246, India
| | - Arabinda Chaudhuri
- Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, West Bengal, 741246, India
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Basirjafar P, Jafarzadeh A, Salimian J. Leptin/LPS-treated dendritic cells reduce the expression of genes involved in tumor tissue metastasis and angiogenesis in an animal model of breast cancer. Immunol Res 2024; 73:2. [PMID: 39658676 DOI: 10.1007/s12026-024-09564-8] [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: 09/27/2024] [Accepted: 11/07/2024] [Indexed: 12/12/2024]
Abstract
Leptin, an immune-regulating protein, enhances the maturation of dendritic cells (DCs). We previously demonstrated that leptin and lipopolysaccharide (LPS) promote the expression of co-stimulatory molecules on the surface of DCs. Leptin/LPS-treated DCs increased T cell responses against 4T1 breast cancer in mice. Therefore, in the present study, we investigate the effects of a DC vaccine treated with leptin and LPS on the genes involved in tumor metastasis, angiogenesis, and related cytokines in a mouse model of breast cancer. Tumor induction was achieved through subcutaneous injection of 4T1 cells into syngeneic mice. On days 12 and 19, the mouse groups received the DC vaccine treated with leptin and a combination of leptin and LPS. After sacrificing the mice on day 26, the levels of IL-6 and IL-33 in the serum were assayed using the ELISA technique, and the expression levels of the VEGF, CCL2, MMP9, and CCL5 genes in the tumors were measured by Real-Time PCR. Compared to untreated tumor-bearing mice, the leptin-treated mature DC (mDC) group exhibited a significant reduction in the expression of MMP9 (0.33-fold, p = 0.01) and CCL5 (0.81-fold, p = 0.02). The leptin-LPS-treated mDC group showed decreased expression of genes involved in metastasis and tumor growth, including VEGF (0.72-fold, p = 0.03), MMP9 (0.26-fold, p = 0.001), and CCL5 (0.3-fold, p = 0.006), indicating more efficient prevention of metastasis. The CCL2 gene expression levels in both treatment groups showed a slight decreasing trend, but these changes were not statistically significant. The leptin-treated mDC group reduced IL-6 production by approximately 16% (p = 0.02), while treatment with the leptin-LPS-treated mDC significantly decreased IL-6 production by approximately 22% (p = 0.01) and increased IL-33 production by approximately 42% (p = 0.03). The findings of the present study indicate that the leptin-LPS-treated mDC vaccine group reduced the expression of genes and cytokines involved in metastasis and angiogenesis, demonstrating greater efficacy compared to the leptin-treated mDC vaccine group.
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Affiliation(s)
- Pedram Basirjafar
- Applied Virology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Jafar Salimian
- Applied Virology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Okwor V, Okwor CJ, Ukwuoma M, Nweke M. Effectiveness of combined targeted and hormonal therapies for post-menopausal women with hormone receptor-positive and HER2-negative advanced breast cancer: A systematic review and meta-analysis of RCTs. J Oncol Pharm Pract 2024:10781552241279019. [PMID: 39295518 DOI: 10.1177/10781552241279019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/21/2024]
Abstract
OBJECTIVE we aim to synthesize available evidence on the effectiveness of hormonal plus targeted therapies for post-menopausal women with hormone receptor-positive and HER2-negative advanced breast cancer. DATA SOURCES AND METHODS We searched the following databases: Medline, PubMed, Cochrane Library, CINAHL, Web of Science, Scopus, and African Journal. Only studies that investigated the effectiveness of hormonal therapy combined with targeted therapy for HR+/HER2- advanced breast cancer treatment were included. The outcomes were progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). A random-effect meta-analysis model was employed. Statistical analysis was performed using Comprehensive Meta-analysis version 3. RESULTS 24 studies were included in the meta-analysis with an overall sample size of 7635. Median PFS, OS and ORR were found to be significantly increased in the combination group compared to hormonal monotherapy [SMD = 6.072 (95% CI = 3.785-8.360), p < 0.001], [SMD = 1.614 (95% CI = 0.139-3.089), p = 0.032] and [OR = 1.584 (CI 1.134-2.213), p = 0.007] respectively. Subgroup analysis showed a significant difference in PFS and ORR between patients who received "hormonal therapy + CDK4/6 inhibitors" vs hormonal therapy only [SMD = 6.015 (CI 3.069-8.960), p < 0.001], (OR = 1.828 (CI 1.030-3.243), p = 0.039] respectively. CONCLUSION Compared with hormonal monotherapy, targeted plus hormonal therapy significantly improves PFS, OS and ORR in postmenopausal women with HR+/HER2- advanced breast cancer.
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Affiliation(s)
- Vitalis Okwor
- Department of Radiation and Clinical Oncology, University of Nigeria Teaching Hospital, Enugu, Nigeria
| | - Chika Juliet Okwor
- Department of Chemical Pathology, College of Medicine, University of Nigeria Ituku-Ozalla Campus, Enugu, Nigeria
| | - Maryjane Ukwuoma
- Department of Physiotherapy, University of Nigeria Teaching Hospital, Enugu, Enugu
| | - Martins Nweke
- Department of Physiotherapy, Evangel University Akaeze, Enugu, Nigeria
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Konnerth D, Gaasch A, Westphalen CB, Heinrich K, Niyazi M, Eze C, Rogowski P, Marschner S, Zinn A, Belka C, Corradini S, Schönecker S. Targeted RT study: results on early toxicity of targeted therapies and radiotherapy. Radiat Oncol 2024; 19:113. [PMID: 39210363 PMCID: PMC11363597 DOI: 10.1186/s13014-024-02494-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 07/22/2024] [Indexed: 09/04/2024] Open
Abstract
PURPOSE/OBJECTIVE Currently, there are few prospective data on the tolerability of combining targeted therapies (TT) with radiation therapy (RT). The objective of this prospective study was to assess the feasibility and toxicity of pairing RT with concurrent TT in cancer patients. The aim was to enhance the existing evidence base for the simultaneous administration of targeted substances together with radiotherapy. METHODS Prospective study enrollment was conducted at a single institution between March 1, 2020, and December 31, 2021, for all patients diagnosed with histologically confirmed cancer who underwent external beam radiotherapy in combination with targeted therapy. The study, known as the "targeted RT study," was registered in the German Clinical Trials Register under DRKS00026193. Systematic documentation of the toxicity profiles of different targeted therapies was performed, and the assessment of acute toxicity followed the guidelines of the National Cancer Institute Common Terminology Criteria for Adverse Events Version v5.0. RESULTS A total of 334 patients underwent 683 radiation therapy series. During the course of RT, 51 different TT substances were concurrently administered. External beam radiotherapy was employed for various anatomical sites. The combination of RT and concurrent TT administration was generally well tolerated, with no instances of severe acute toxicity observed. The most commonly reported toxicity was fatigue, ranging from mild to moderate Common Terminology Criteria for Adverse Events (CTCAE) °I-°III. Other frequently observed toxicities included dermatitis, dyspnea, dysphagia, and dry cough. No toxicity greater than moderate severity was recorded at any point. In only 32 patients (4.7% of evaluated RT series), the concurrent substance administration was discontinued due to side effects. However, these side effects did not exceed mild severity according to CTCAE, suggesting that discontinuation was a precautionary measure. Only one patient receiving Imatinib treatment experienced a severe CTCAE °III side effect, leading to discontinuation of the concurrent substance due to the sudden occurrence of melaena during RT. CONCLUSION In conclusion, the current study did not demonstrate a significant increase or additional toxicity when combining radiotherapy and concurrent targeted therapy. However, additional research is required to explore the specific toxicity profiles of the various substances that can be utilized in this context. TRIAL REGISTRATION NUMBER DRKS00026193. Date of registration 12/27/2022 (retrospectively registered).
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Affiliation(s)
- Dinah Konnerth
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.
| | - Aurelie Gaasch
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - C Benedikt Westphalen
- Partner Site Munich, German Cancer Consortium (DKTK), Munich, Germany
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
- Comprehensive Cancer Center (CCC Munich LMU), University Hospital, LMU Munich, Munich, Germany
| | - Kathrin Heinrich
- Partner Site Munich, German Cancer Consortium (DKTK), Munich, Germany
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Maximilian Niyazi
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
- Department of Radiation Oncology, University Hospital Tübingen, Tübingen, Germany
| | - Chukwuka Eze
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Paul Rogowski
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Sebastian Marschner
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
- Partner Site Munich, German Cancer Consortium (DKTK), Munich, Germany
| | - Annemarie Zinn
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Claus Belka
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
- Partner Site Munich, German Cancer Consortium (DKTK), Munich, Germany
- Bavarian Cancer Research Center (BZKF), Munich, Germany
| | - Stefanie Corradini
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Stephan Schönecker
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
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Mitsui A, Iioka H, Ling Y, Okuda S, Kurose A, Schopperle M, Kondo T, Sakaguchi M, Saito K, Kondo E. Pathological and Biological Significance of the Specific Glycan, TRA-1-60, on Aggressive Gastric Adenocarcinoma. J Transl Med 2024; 104:102073. [PMID: 38718982 DOI: 10.1016/j.labinv.2024.102073] [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: 01/22/2024] [Revised: 04/16/2024] [Accepted: 04/30/2024] [Indexed: 05/27/2024] Open
Abstract
The glycans form a unique complex on the surface of cancer cells and play a pivotal role in tumor progression, impacting proliferation, invasion, and metastasis. TRA-1-60 is a glycan that was identified as a critical marker for the establishment of fully reprogrammed inducible pluripotent stem cells. Its expression has been detected in multiple cancer tissues, including embryonal carcinoma, prostate cancer, and pancreatic cancer, but the biological and pathological characterization of TRA-1-60-expressing tumor cells remains unclear within various types of malignancies. Here, we report the biological characteristics of TRA-1-60-expressing gastric cancer cells, especially those with its cell surface expression, and the therapeutic significance of targeting TRA-1-60. The cells with cell membrane expression of TRA-1-60 were mainly observed in the invasive area of patient gastric cancer tissues and correlated with advanced stages of the disease based on histopathological and clinicopathological analyses. In vitro analysis using a scirrhous gastric adenocarcinoma line, HSC-58, which highly expresses TRA-1-60 on its plasma membrane, revealed increased stress-resistant mechanisms, supported by the upregulation of glutathione synthetase and NCF-1 (p47phox) via lipid-ROS regulatory pathways, as detected by RNA-seq analysis followed by oxidative stress gene profiling. Our in vivo therapeutic study using the TRA-1-60-targeting antibody-drug conjugate, namely, Bstrongomab-conjugated monomethyl auristatin E, showed robust efficacy in a mouse model of peritoneal carcinomatosis induced by intraperitoneal xenograft of HSC-58, by markedly reducing massive tumor ascites. Thus, targeting the specific cell surface glycan, TRA-1-60, shows a significant therapeutic impact in advanced-stage gastric cancers.
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Affiliation(s)
- Ayaka Mitsui
- Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hidekazu Iioka
- Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yiwei Ling
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shujiro Okuda
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Akira Kurose
- Department of Anatomic Pathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | | | - Tomoko Kondo
- Department of Molecular Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Masakiyo Sakaguchi
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Ken Saito
- Department of Clinical Engineering and Medical Technology, Niigata University of Health and Welfare, Niigata, Japan
| | - Eisaku Kondo
- Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Division of Tumor Pathology, NIR-PIT Research Institute, Kansai Medical University, Osaka, Japan.
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Coelho LL, Vianna MM, da Silva DM, Gonzaga BMDS, Ferreira RR, Monteiro AC, Bonomo AC, Manso PPDA, de Carvalho MA, Vargas FR, Garzoni LR. Spheroid Model of Mammary Tumor Cells: Epithelial-Mesenchymal Transition and Doxorubicin Response. BIOLOGY 2024; 13:463. [PMID: 39056658 PMCID: PMC11273983 DOI: 10.3390/biology13070463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/12/2024] [Accepted: 05/13/2024] [Indexed: 07/28/2024]
Abstract
Breast cancer is the most prevalent cancer among women worldwide. Therapeutic strategies to control tumors and metastasis are still challenging. Three-dimensional (3D) spheroid-type systems more accurately replicate the features of tumors in vivo, working as a better platform for performing therapeutic response analysis. This work aimed to characterize the epithelial-mesenchymal transition and doxorubicin (dox) response in a mammary tumor spheroid (MTS) model. We evaluated the doxorubicin treatment effect on MCF-7 spheroid diameter, cell viability, death, migration and proteins involved in the epithelial-mesenchymal transition (EMT) process. Spheroids were also produced from tumors formed from 4T1 and 67NR cell lines. MTSs mimicked avascular tumor characteristics, exhibited adherens junction proteins and independently produced their own extracellular matrix. Our spheroid model supports the 3D culturing of cells isolated from mice mammary tumors. Through the migration assay, we verified a reduction in E-cadherin expression and an increase in vimentin expression as the cells became more distant from spheroids. Dox promoted cytotoxicity in MTSs and inhibited cell migration and the EMT process. These results suggest, for the first time, that this model reproduces aspects of the EMT process and describes the potential of dox in inhibiting the metastatic process, which can be further explored.
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Affiliation(s)
- Laura Lacerda Coelho
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil; (L.L.C.); (M.M.V.); (D.M.d.S.); (B.M.d.S.G.); (R.R.F.)
| | - Matheus Menezes Vianna
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil; (L.L.C.); (M.M.V.); (D.M.d.S.); (B.M.d.S.G.); (R.R.F.)
| | - Debora Moraes da Silva
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil; (L.L.C.); (M.M.V.); (D.M.d.S.); (B.M.d.S.G.); (R.R.F.)
| | - Beatriz Matheus de Souza Gonzaga
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil; (L.L.C.); (M.M.V.); (D.M.d.S.); (B.M.d.S.G.); (R.R.F.)
| | - Roberto Rodrigues Ferreira
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil; (L.L.C.); (M.M.V.); (D.M.d.S.); (B.M.d.S.G.); (R.R.F.)
| | - Ana Carolina Monteiro
- Laboratory of Osteo and Tumor Immunology, Department of Immunobiology, Fluminense Federal University (UFF), Rio de Janeiro 24020-150, Brazil;
- Thymus Research Laboratory, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil;
| | - Adriana Cesar Bonomo
- Thymus Research Laboratory, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil;
| | - Pedro Paulo de Abreu Manso
- Laboratory of Pathology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil;
| | | | - Fernando Regla Vargas
- Laboratory of Epidemiology of Congenital Malformations, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil;
| | - Luciana Ribeiro Garzoni
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil; (L.L.C.); (M.M.V.); (D.M.d.S.); (B.M.d.S.G.); (R.R.F.)
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Egbulefu C, Black K, Su X, Karmakar P, Habimana-Griffin L, Sudlow G, Prior J, Chukwu E, Zheleznyak A, Xu B, Xu Y, Esser A, Mixdorf M, Moss E, Manion B, Reed N, Gubin M, Lin CY, Schreiber R, Weilbaecher K, Achilefu S. Induction of complementary immunogenic necroptosis and apoptosis cell death pathways inhibits cancer metastasis and relapse. RESEARCH SQUARE 2024:rs.3.rs-3992212. [PMID: 38558990 PMCID: PMC10980095 DOI: 10.21203/rs.3.rs-3992212/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Interactions of light-sensitive drugs and materials with Cerenkov radiation-emitting radiopharmaceuticals generate cytotoxic reactive oxygen species (ROS) to inhibit localized and disseminated cancer progression, but the cell death mechanisms underlying this radionuclide stimulated dynamic therapy (RaST) remain elusive. Using ROS-regenerative nanophotosensitizers coated with a tumor-targeting transferrin-titanocene complex (TiO2-TC-Tf) and radiolabeled 2-fluorodeoxyglucose (18FDG), we found that adherent dying cells maintained metabolic activity with increased membrane permeabilization. Mechanistic assessment of these cells revealed that RaST activated the expression of RIPK-1 and RIPK-3, which mediate necroptosis cell death. Subsequent recruitment of the nuclear factors kappa B and the executioner mixed lineage kinase domain-like pseudo kinase (MLKL) triggered plasma membrane permeabilization and pore formation, respectively, followed by the release of cytokines and immunogenic damage-associated molecular patterns (DAMPs). In immune-deficient breast cancer models with adequate stroma and growth factors that recapitulate the human tumor microenvironment, RaST failed to inhibit tumor progression and the ensuing lung metastasis. A similar aggressive tumor model in immunocompetent mice responded to RaST, achieving a remarkable partial response (PR) and complete response (CR) with no evidence of lung metastasis, suggesting active immune system engagement. RaST recruited antitumor CD11b+, CD11c+, and CD8b+ effector immune cells after initiating dual immunogenic apoptosis and necroptosis cell death pathways in responding tumors in vivo. Over time, cancer cells upregulated the expression of negative immune regulating cytokine (TGF-β) and soluble immune checkpoints (sICP) to challenge RaST effect in the CR mice. Using a signal-amplifying cancer-imaging agent, LS301, we identified latent minimal residual disseminated tumors in the lymph nodes (LNs) of the CR group. Despite increased protumor immunogens in the CR mice, RaST prevented cancer relapse and metastasis through dynamic redistribution of ROS-regenerative TiO2 from bones at the early treatment stage to the spleen and LNs, maintaining active immunity against cancer progression and migration. This study reveals the immune-mechanistic underpinnings of RaST-mediated antitumor immune response and highlights immunogenic reprogramming of tumors in response to RaST. Overcoming apoptosis resistance through complementary necroptosis activation paves the way for strategic drug combinations to improve cancer treatment.
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Affiliation(s)
- Christopher Egbulefu
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
- Department of Biomedical Engineering, The University of Texas Southwestern Medical Center, Dallas, TX 75235-9397, USA
| | - Kvar Black
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | - Xinming Su
- Department of Medicine, Washington University in St. Louis, MO 63110, USA
| | - Partha Karmakar
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | | | - Gail Sudlow
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | - Julie Prior
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | - Ezeugo Chukwu
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | - Alex Zheleznyak
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | - Baogang Xu
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | - Yalin Xu
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | - Alison Esser
- Department of Medicine, Washington University in St. Louis, MO 63110, USA
| | - Matthew Mixdorf
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | - Evan Moss
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | - Brad Manion
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | - Nathan Reed
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
| | - Matthew Gubin
- Department of Pathology and Immunology, Washington University in St. Louis, MO 63110, USA
| | - Chieh-Yu Lin
- Department of Pathology and Immunology, Washington University in St. Louis, MO 63110, USA
| | - Robert Schreiber
- Department of Pathology and Immunology, Washington University in St. Louis, MO 63110, USA
| | | | - Samuel Achilefu
- Department of Radiology, Washington University in St. Louis, MO 63110, USA
- Department of Medicine, Washington University in St. Louis, MO 63110, USA
- Department of Biomedical Engineering, Washington University in St. Louis, MO 63110, USA
- Department of Biomedical Engineering, The University of Texas Southwestern Medical Center, Dallas, TX 75235-9397, USA
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10
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Vo TH, EL-Sherbieny Abdelaal E, Jordan E, O'Donovan O, McNeela EA, Mehta JP, Rani S. miRNAs as biomarkers of therapeutic response to HER2-targeted treatment in breast cancer: A systematic review. Biochem Biophys Rep 2024; 37:101588. [PMID: 38088952 PMCID: PMC10711031 DOI: 10.1016/j.bbrep.2023.101588] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 11/19/2023] [Indexed: 06/16/2024] Open
Abstract
Breast cancer is the most common type of lethal cancer in women globally. Women have a 1 in 8 chance of developing breast cancer in their lifetime. Among the four primary molecular subtypes (luminal A, luminal B, HER2+, and triple-negative), HER2+ accounts for 20-25 % of all breast cancer and is rather aggressive. Although the treatment outcome of HER2+ breast cancer patients has been significantly improved with anti-HER2 agents, primary and acquired drug resistance present substantial clinical issues, limiting the benefits of HER2-targeted treatment. MicroRNAs (miRNAs) play a central role in regulating acquired drug resistance. miRNA are single-stranded, non-coding RNAs of around 20-25 nucleotides, known for essential roles in regulating gene expression at the post-transcriptional level. Increasing evidence has demonstrated that miRNA-mediated alteration of gene expression is associated with tumorigenesis, metastasis, and tumor response to treatment. Comprehensive knowledge of miRNAs as potential markers of drug response can help provide valuable guidance for treatment prognosis and personalized medicine for breast cancer patients.
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Affiliation(s)
- Thanh Hoa Vo
- Department of Science, School of Science and Computing, South East Technological University, Cork Road, Waterford, X91 K0EK, Ireland
- Pharmaceutical and Molecular Biotechnology Research Center, South East Technological University, Cork Road, X91 K0EK, Waterford, Ireland
| | | | - Emmet Jordan
- Department of Oncology, University Hospital Waterford, Dunmore Road, X91 ER8E, Waterford, Ireland
| | - Orla O'Donovan
- Department of Science, School of Science and Computing, South East Technological University, Cork Road, Waterford, X91 K0EK, Ireland
- Pharmaceutical and Molecular Biotechnology Research Center, South East Technological University, Cork Road, X91 K0EK, Waterford, Ireland
| | - Edel A. McNeela
- Department of Science, School of Science and Computing, South East Technological University, Cork Road, Waterford, X91 K0EK, Ireland
- Pharmaceutical and Molecular Biotechnology Research Center, South East Technological University, Cork Road, X91 K0EK, Waterford, Ireland
| | - Jai Prakash Mehta
- Department of Applied Science, South East Technological University, Kilkenny Road, R93 V960, Carlow, Ireland
| | - Sweta Rani
- Department of Science, School of Science and Computing, South East Technological University, Cork Road, Waterford, X91 K0EK, Ireland
- Pharmaceutical and Molecular Biotechnology Research Center, South East Technological University, Cork Road, X91 K0EK, Waterford, Ireland
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11
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Li D, Hu A. LINC-PINT suppresses breast cancer cell proliferation and migration via MEIS2/PPP3CC/NF-κB pathway by sponging miR-576-5p. Am J Med Sci 2024; 367:201-211. [PMID: 37660994 DOI: 10.1016/j.amjms.2023.08.013] [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: 08/04/2022] [Revised: 04/13/2023] [Accepted: 08/29/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND Breast cancer (BCa) is the most frequent malignant tumor in women. Long non-coding RNAs (lncRNAs) have been acknowledged to exert critical regulating functions in various cancers. Long intergenic non-protein coding RNA, p53 induced transcript (LINC-PINT) has been reported to be a chemosensitizer and a tumor suppressor in BCa. However, its downstream molecular mechanism contributing to its tumor-suppressing role remains to be explored in BCa. METHODS LINC-PINT expression in BCa tissues and cells was measured using quantitative real-time polymerase chain reaction (RT-qPCR). The proliferation of transfected BCa cells was examined by counting kit-8 (CCK-8) and EdU assay. The migrating ability of indicate BCa cells was assessed by wound healing assays. Bioinformatics analysis and mechanism experiments such as RNA immunoprecipitation (RIP), RNA pull down assay, and luciferase reporter assay, were applied to demonstrate the downstream targets of LINC-PINT. RESULTS LINC-PINT was downregulated in BCa tissues and cell lines. Overexpression of LINC-PINT suppressed BCa cell proliferation and migration. LINC-PINT could interact with miR-576-5p to upregulate Meis homeobox 2 (MEIS2) that positively regulated protein phosphatase 3 catalytic subunit gamma (PPP3CC) by inactivating the nuclear factor-κB (NF-κB) pathway. CONCLUSIONS These findings elucidated the anti-tumor role of LINC-PINT in BCa via the miR-576-5p/MEIS2/PPP3CC/NF-κB axis, which suggested that LINC-PINT might serve as a potential therapeutic target for BCa.
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Affiliation(s)
- Daohong Li
- Department of Pathology, Henan Provincial People's Hospital, Jinshui District, Zhengzhou, Henan, China
| | - Aixia Hu
- Department of Pathology, Henan Provincial People's Hospital, Jinshui District, Zhengzhou, Henan, China.
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12
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Asano S, Ono A, Baba K, Uehara T, Sakamoto K, Hayata-Takano A, Nakazawa T, Yanamoto S, Tanimoto K, Hashimoto H, Ago Y. Blockade of vasoactive intestinal peptide receptor 2 (VIPR2) signaling suppresses cyclin D1-dependent cell-cycle progression in MCF-7 cells. J Pharmacol Sci 2024; 154:139-147. [PMID: 38395514 DOI: 10.1016/j.jphs.2024.01.002] [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: 11/01/2023] [Revised: 12/28/2023] [Accepted: 01/05/2024] [Indexed: 02/25/2024] Open
Abstract
Vasoactive intestinal peptide (VIP) receptor 2 (VIPR2) is a G protein-coupled receptor that binds to Gαs, Gαi, and Gαq proteins to regulate various downstream signaling molecules, such as protein kinase A (PKA), phosphatidylinositol 3-kinase (PI3K), and phospholipase C. In this study, we examined the role of VIPR2 in cell cycle progression. KS-133, a newly developed VIPR2-selective antagonist peptide, attenuated VIP-induced cell proliferation in MCF-7 cells. The percentage of cells in the S-M phase was decreased in MCF-7 cells treated with KS-133. KS-133 in the presence of VIP decreased the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and glycogen synthase kinase-3β (GSK3β), resulting in a decrease in cyclin D1 levels. In MCF-7 cells stably-expressing VIPR2, KS-133 decreased PI3K activity and cAMP levels. Treatment with the ERK-specific kinase (MEK) inhibitor U0126 and the class I PI3K inhibitor ZSTK474 decreased the percentage of cells in the S phase. KS-133 reduced the percentage of cells in the S phase more than treatment with U0126 or ZSTK474 alone and did not affect the effect of the mixture of these inhibitors. Our findings suggest that VIPR2 signaling regulates cyclin D1 levels through the cAMP/PKA/ERK and PI3K/AKT/GSK3β pathways, and mediates the G1/S transition to control cell proliferation.
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Affiliation(s)
- Satoshi Asano
- Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan; School of Dentistry, Hiroshima University, Hiroshima, 734-8553, Japan.
| | - Ami Ono
- Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan; Department of Orthodontics and Craniofacial Developmental Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Kaede Baba
- School of Dentistry, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Teru Uehara
- Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan; Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Kotaro Sakamoto
- Research & Development Department, Ichimaru Pharcos Company Limited, 318-1 Asagi, Motosu, Gifu, 501-0475, Japan
| | - Atsuko Hayata-Takano
- Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, 565-0871, Japan; Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, University of Fukui, Osaka, 565-0871, Japan
| | - Takanobu Nakazawa
- Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan; Laboratory of Molecular Biology, Department of Bioscience, Graduate School of Life Sciences, Tokyo University of Agriculture, Tokyo, 156-8502, Japan
| | - Souichi Yanamoto
- School of Dentistry, Hiroshima University, Hiroshima, 734-8553, Japan; Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Kotaro Tanimoto
- School of Dentistry, Hiroshima University, Hiroshima, 734-8553, Japan; Department of Orthodontics and Craniofacial Developmental Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Hitoshi Hashimoto
- Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, University of Fukui, Osaka, 565-0871, Japan; Division of Bioscience, Institute for Datability Science, Osaka University, Osaka, 565-0871, Japan; Transdimensional Life Imaging Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, 565-0871, Japan; Department of Molecular Pharmaceutical Science, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Yukio Ago
- Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan; School of Dentistry, Hiroshima University, Hiroshima, 734-8553, Japan.
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13
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Del Campo Fonseca A, Ahmed D. Ultrasound robotics for precision therapy. Adv Drug Deliv Rev 2024; 205:115164. [PMID: 38145721 DOI: 10.1016/j.addr.2023.115164] [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: 09/30/2023] [Revised: 12/07/2023] [Accepted: 12/22/2023] [Indexed: 12/27/2023]
Abstract
In recent years, the application of microrobots in precision therapy has gained significant attention. The small size and maneuverability of these micromachines enable them to potentially access regions that are difficult to reach using traditional methods; thus, reducing off-target toxicities and maximizing treatment effectiveness. Specifically, acoustic actuation has emerged as a promising method to exert control. By harnessing the power of acoustic energy, these small machines potentially navigate the body, assemble at the desired sites, and deliver therapies with enhanced precision and effectiveness. Amidst the enthusiasm surrounding these miniature agents, their translation to clinical environments has proven difficult. The primary objectives of this review are threefold: firstly, to offer an overview of the fundamental acoustic principles employed in the field of microrobots; secondly, to assess their current applications in medical therapies, encompassing tissue targeting, drug delivery or even cell infiltration; and lastly, to delve into the continuous efforts aimed at integrating acoustic microrobots into in vivo applications.
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Affiliation(s)
- Alexia Del Campo Fonseca
- Department of Mechanical and Process Engineering, Acoustic Robotics Systems Lab, ETH Zurich, Säumerstrasse 4, 8803 Rüschlikon, Switzerland.
| | - Daniel Ahmed
- Department of Mechanical and Process Engineering, Acoustic Robotics Systems Lab, ETH Zurich, Säumerstrasse 4, 8803 Rüschlikon, Switzerland.
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14
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Musket A, Davern S, Elam BM, Musich PR, Moorman JP, Jiang Y. The application of radionuclide therapy for breast cancer. FRONTIERS IN NUCLEAR MEDICINE (LAUSANNE, SWITZERLAND) 2024; 3:1323514. [PMID: 39355029 PMCID: PMC11440853 DOI: 10.3389/fnume.2023.1323514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 12/27/2023] [Indexed: 10/03/2024]
Abstract
Radionuclide-mediated diagnosis and therapy have emerged as effective and low-risk approaches to treating breast cancer. Compared to traditional anatomic imaging techniques, diagnostic radionuclide-based molecular imaging systems exhibit much greater sensitivity and ability to precisely illustrate the biodistribution and metabolic processes from a functional perspective in breast cancer; this transitions diagnosis from an invasive visualization to a noninvasive visualization, potentially ensuring earlier diagnosis and on-time treatment. Radionuclide therapy is a newly developed modality for the treatment of breast cancer in which radionuclides are delivered to tumors and/or tumor-associated targets either directly or using delivery vehicles. Radionuclide therapy has been proven to be eminently effective and to exhibit low toxicity when eliminating both primary tumors and metastases and even undetected tumors. In addition, the specific interaction between the surface modules of the delivery vehicles and the targets on the surface of tumor cells enables radionuclide targeting therapy, and this represents an exceptional potential for this treatment in breast cancer. This article reviews the development of radionuclide molecular imaging techniques that are currently employed for early breast cancer diagnosis and both the progress and challenges of radionuclide therapy employed in breast cancer treatment.
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Affiliation(s)
- Anna Musket
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Sandra Davern
- Oak Ridge National Laboratory, Oak Ridge, TN, United States
| | - Brianna M Elam
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Philip R Musich
- Department of Biomedical Science, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Jonathan P Moorman
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Yong Jiang
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
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15
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Mahmoudi G, Ehteshaminia Y, Kokhaei P, Jalali SF, Jadidi-Niaragh F, Pagheh AS, Enderami SE, Kenari SA, Hassannia H. Enhancement of targeted therapy in combination with metformin on human breast cancer cell lines. Cell Commun Signal 2024; 22:10. [PMID: 38167105 PMCID: PMC10763326 DOI: 10.1186/s12964-023-01446-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 12/18/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Breast cancer remains a primary global health concern due to its limited treatment options, frequent disease recurrence, and high rates of morbidity and mortality. Thereby, there is a need for more effective treatment approaches. The proposal suggests that the combination of targeted therapy with other antitumoral agents could potentially address drug resistance. In this study, we examined the antitumoral effect of combining metformin, an antidiabetic drug, with targeted therapies, including tamoxifen for estrogen receptor-positive (MCF-7), trastuzumab for HER2-positive (SKBR-3), and antibody against ROR1 receptor for triple-negative breast cancer (MDA-MB-231). METHODS Once the expression of relevant receptors on each cell line was confirmed and appropriate drug concentrations were selected through cytotoxicity assays, the antitumor effects of both monotherapy and combination therapy on colony formation, migration, invasion were assessed in in vitro as well as tumor area and metastatic potential in ex ovo Chick chorioallantoic membrane (CAM) models. RESULTS The results exhibited the enhanced effects of tamoxifen when combined with targeted therapy. This combination effectively inhibited cell growth, colony formation, migration, and invasion in vitro. Additionally, it significantly reduced tumor size and metastatic potential in an ex ovo CAM model. CONCLUSIONS The findings indicate that a favorable strategy to enhance the efficacy of breast cancer treatment would be to combine metformin with targeted therapies.
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Affiliation(s)
- Ghazal Mahmoudi
- Student Research Committee, Amol School of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Yahya Ehteshaminia
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Parviz Kokhaei
- Department of Immunology, Arak University of Medical Sciences, Arak, Iran
| | - Seyedeh Farzaneh Jalali
- Department of Hematology, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Abdol Sattar Pagheh
- Infectious Diseases Research Center, Birjand University of Medical Science, Birjand, Iran
| | - Seyed Ehsan Enderami
- Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Saeid Abedian Kenari
- Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hadi Hassannia
- Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- Department of Paramedicine, Amol School of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran.
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16
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Srivastava S, Jain P. Computational Approaches: A New Frontier in Cancer Research. Comb Chem High Throughput Screen 2024; 27:1861-1876. [PMID: 38031782 DOI: 10.2174/0113862073265604231106112203] [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: 06/30/2023] [Revised: 09/08/2023] [Accepted: 09/21/2023] [Indexed: 12/01/2023]
Abstract
Cancer is a broad category of disease that can start in virtually any organ or tissue of the body when aberrant cells assault surrounding organs and proliferate uncontrollably. According to the most recent statistics, cancer will be the cause of 10 million deaths worldwide in 2020, accounting for one death out of every six worldwide. The typical approach used in anti-cancer research is highly time-consuming and expensive, and the outcomes are not particularly encouraging. Computational techniques have been employed in anti-cancer research to advance our understanding. Recent years have seen a significant and exceptional impact on anticancer research due to the rapid development of computational tools for novel drug discovery, drug design, genetic studies, genome characterization, cancer imaging and detection, radiotherapy, cancer metabolomics, and novel therapeutic approaches. In this paper, we examined the various subfields of contemporary computational techniques, including molecular docking, artificial intelligence, bioinformatics, virtual screening, and QSAR, and their applications in the study of cancer.
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Affiliation(s)
- Shubham Srivastava
- Department of Pharmacy, IIMT College of Pharmacy, Uttar Pradesh, 201310, India
| | - Pushpendra Jain
- Department of Pharmacy, IIMT College of Pharmacy, Uttar Pradesh, 201310, India
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17
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Thanasan S, Sukhakul K, Chitpakdee S, Kitkumthorn N. Diagnostic Accuracy of Immunohistochemistry for HER2-Positive Breast Cancer. Asian Pac J Cancer Prev 2023; 24:4321-4327. [PMID: 38156869 PMCID: PMC10909106 DOI: 10.31557/apjcp.2023.24.12.4321] [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: 08/31/2023] [Accepted: 12/07/2023] [Indexed: 01/03/2024] Open
Abstract
OBJECTIVE Currently, human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells are diagnosed under the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) 2018 guidelines. The guideline combined the results of in situ hybridization (DISH) and immunohistochemistry (IHC) techniques. The IHC technique is easy, cheap, and suitable for developing country. Therefore, in this study, we validated the use of IHC alone compared to the results of HER2 amplification under ASCO/CAP 2018 guidelines in diagnosed HER2 positive breast cancer cells. METHODS A total of 510 breast cancer tissue samples from Rajavithi Hospital in Bangkok, Thailand, from January 1st, 2022, to May 31st, 2023, were analyzed by IHC, followed by dual ISH (DISH). We selected 58 samples of IHC equivocal (score 2+) and 98 samples of IHC positive (score 3+) to analyze the diagnostic values by comparing them to the results of HER2 amplification. RESULTS The HER2 IHC score was found to agree with HER2 amplification with a sensitivity of 87.96%, a specificity of 93.75%, a positive predictive value of 96.94%, a negative predictive value of 77.59%, a positive likelihood ratio of 14.07, a negative likelihood ratio of 0.13, and an accuracy of 89.74%. CONCLUSION The promising outcomes suggest that a positive IHC test result (score 3+) could potentially stand alone for patients with breast cancer undergoing anti-HER2 treatment, even without DISH confirmation.
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Affiliation(s)
- Siwaporn Thanasan
- Pathology Department, Rajavithi Hospital, Phayathai Road, Ratchathewi, Bangkok, Thailand.
| | - Kweekrong Sukhakul
- Pathology Department, Rajavithi Hospital, Phayathai Road, Ratchathewi, Bangkok, Thailand.
| | - Sakchai Chitpakdee
- Pathology Department, Rajavithi Hospital, Phayathai Road, Ratchathewi, Bangkok, Thailand.
| | - Nakarin Kitkumthorn
- Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand.
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Maugeri S, Sibbitts J, Privitera A, Cardaci V, Di Pietro L, Leggio L, Iraci N, Lunte SM, Caruso G. The Anti-Cancer Activity of the Naturally Occurring Dipeptide Carnosine: Potential for Breast Cancer. Cells 2023; 12:2592. [PMID: 37998326 PMCID: PMC10670273 DOI: 10.3390/cells12222592] [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: 09/25/2023] [Revised: 10/27/2023] [Accepted: 11/06/2023] [Indexed: 11/25/2023] Open
Abstract
Carnosine is an endogenous dipeptide composed of β-alanine and L-histidine, possessing a multimodal pharmacodynamic profile that includes anti-inflammatory and anti-oxidant activities. Carnosine has also shown its ability to modulate cell proliferation, cell cycle arrest, apoptosis, and even glycolytic energy metabolism, all processes playing a key role in the context of cancer. Cancer is one of the most dreaded diseases of the 20th and 21st centuries. Among the different types of cancer, breast cancer represents the most common non-skin cancer among women, accounting for an estimated 15% of all cancer-related deaths in women. The main aim of the present review was to provide an overview of studies on the anti-cancer activity of carnosine, and in particular its activity against breast cancer. We also highlighted the possible advantages and limitations involved in the use of this dipeptide. The first part of the review entailed a brief description of carnosine's biological activities and the pathophysiology of cancer, with a focus on breast cancer. The second part of the review described the anti-tumoral activity of carnosine, for which numerous studies have been carried out, especially at the preclinical level, showing promising results. However, only a few studies have investigated the therapeutic potential of this dipeptide for breast cancer prevention or treatment. In this context, carnosine has shown to be able to decrease the size of cancer cells and their viability. It also reduces the levels of vascular endothelial growth factor (VEGF), cyclin D1, NAD+, and ATP, as well as cytochrome c oxidase activity in vitro. When tested in mice with induced breast cancer, carnosine proved to be non-toxic to healthy cells and exhibited chemopreventive activity by reducing tumor growth. Some evidence has also been reported at the clinical level. A randomized phase III prospective placebo-controlled trial showed the ability of Zn-carnosine to prevent dysphagia in breast cancer patients undergoing adjuvant radiotherapy. Despite this evidence, more preclinical and clinical studies are needed to better understand carnosine's anti-tumoral activity, especially in the context of breast cancer.
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Affiliation(s)
- Salvatore Maugeri
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy
| | - Jay Sibbitts
- Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS 66047, USA
- Department of Chemistry, University of Kansas, Lawrence, KS 66047, USA
| | - Anna Privitera
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | - Vincenzo Cardaci
- Scuola Superiore di Catania, University of Catania, 95123 Catania, Italy
- Vita-Salute San Raffaele University, 20132 Milano, Italy
| | - Lucia Di Pietro
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy
- Scuola Superiore di Catania, University of Catania, 95123 Catania, Italy
| | - Loredana Leggio
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | - Nunzio Iraci
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | - Susan M. Lunte
- Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS 66047, USA
- Department of Chemistry, University of Kansas, Lawrence, KS 66047, USA
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA
| | - Giuseppe Caruso
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy
- Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute-IRCCS, 94018 Troina, Italy
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19
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Jallah JK, Dweh TJ, Anjankar A, Palma O. A Review of the Advancements in Targeted Therapies for Breast Cancer. Cureus 2023; 15:e47847. [PMID: 38022130 PMCID: PMC10679843 DOI: 10.7759/cureus.47847] [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: 09/23/2023] [Accepted: 10/28/2023] [Indexed: 12/01/2023] Open
Abstract
Breast cancer, the second-most common and lethal disease in women, poses a severe danger to global health. Breast cancer rates continue to climb despite advances in medical technology. Predictions indicate that by 2040, there will be more than three million new cases yearly. Targeted medicines have experienced a profound transformation in treating breast cancer, allowing for individualized strategies that lessen side effects and improve patient outcomes. This thorough analysis gives a rigorous investigation of current developments in breast cancer-targeted treatments. It carefully examines several subtypes, including hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative breast cancer (TNBC), recognizing the illness' fundamental variety. It offers specialized treatment plans catered to each subtype's particular traits. The review also examines how precise genetic abnormalities like BRCA1/2 and PIK3CA mutations and molecular profiling facilitate therapy selection. Monoclonal antibodies and small molecule inhibitors are some of the targeted medicines examined in the study. It explains how each of these treatments works and supports its findings with data from clinical trials. It also considers potential new medications and addresses persistent problems, such as resistance mechanisms, chances for combining therapies, and cutting-edge patient classification techniques. This study seeks to give healthcare professionals, researchers, and patients a thorough overview of the recent advancements in breast cancer-targeted therapy by drawing on the opinions of top authorities in the area. The coordinated effort aims to create customized, efficient therapies, eventually bolstering the battle against this powerful illness.
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Affiliation(s)
- John Kessellie Jallah
- Department of Biochemistry, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Tuward J Dweh
- Department of Biotechnology, C.V. Raman Global University, Bhubaneswar, IND
| | - Ashish Anjankar
- Department of Biochemistry, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Ogiza Palma
- Department of Biochemistry, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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20
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Giacomini A, Turati M, Grillo E, Rezzola S, Ghedini GC, Schuind AC, Foglio E, Maccarinelli F, Faletti J, Filiberti S, Chambery A, Valletta M, Melocchi L, Gofflot S, Chiavarina B, Turtoi A, Presta M, Ronca R. The PTX3/TLR4 autocrine loop as a novel therapeutic target in triple negative breast cancer. Exp Hematol Oncol 2023; 12:82. [PMID: 37749607 PMCID: PMC10519006 DOI: 10.1186/s40164-023-00441-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 09/04/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUND The pattern recognition receptor long pentraxin-3 (PTX3) plays conflicting roles in cancer by acting as an oncosuppressor or as a pro-tumor mediator depending on tumor context. Triple negative breast cancer (TNBC) represents the most aggressive histotype of breast cancer, characterized by the lack of efficacious therapeutic targets/approaches and poor prognosis. Thus, the characterization of new molecular pathways and/or alternative druggable targets is of great interest in TNBC. METHODS The expression of PTX3 in BC tumor samples and in BC cell lines has been analyzed using the Gene Expression-Based Outcome for Breast Cancer Online (GOBO), qPCR, Western blot and ELISA assay. The contribution of tumor and stromal cells to PTX3 production in TNBC was assessed by analyzing single cell RNA sequencing data and RNAscope performed on TNBC tumor samples. In order to investigate the effects of PTX3 in TNBC, different cell lines were engineered to knock-down (MDA-MB-231 and BT549 cells) or overexpress (MDA-MB-468 and E0771 cells) PTX3. Finally, using these engineered cells, in vitro (including gene expression profiling and gene set enrichment analyses) and in vivo (orthotopic tumor models in immune-compromised and immune competent mice) analyses were performed to assess the role and the molecular mechanism(s) exerted by PTX3 in TNBC. RESULTS In silico and experimental data indicate that PTX3 is mainly produced by tumor cells in TNBC and that its expression levels correlate with tumor stage. Accordingly, gene expression and in vitro results demonstrate that PTX3 overexpression confers a high aggressive/proliferative phenotype and fosters stem-like features in TNBC cells. Also, PTX3 expression induces a more tumorigenic potential when TNBC cells are grafted orthotopically in vivo. Conversely, PTX3 downregulation results in a less aggressive behavior of TNBC cells. Mechanistically, our data reveal that PTX3 drives the activation of the pro-tumorigenic Toll-like receptor 4 (TLR4) signaling pathway in TNBC, demonstrating for the first time that the PTX3/TLR4 autocrine stimulation loop contributes to TNBC aggressiveness and that TLR4 inhibition significantly impacts the growth of PTX3-producing TNBC cells. CONCLUSION Altogether, these data shed light on the role of tumor-produced PTX3 in TNBC and uncover the importance of the PTX3/TLR4 axis for therapeutic and prognostic exploitation in TNBC.
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Affiliation(s)
- Arianna Giacomini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
| | - Marta Turati
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Elisabetta Grillo
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Sara Rezzola
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Gaia Cristina Ghedini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Ander Churruca Schuind
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Eleonora Foglio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Federica Maccarinelli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Jessica Faletti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Serena Filiberti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Angela Chambery
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania 'Luigi Vanvitelli', Caserta, Italy
| | - Mariangela Valletta
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania 'Luigi Vanvitelli', Caserta, Italy
| | - Laura Melocchi
- Pathology Unit, Fondazione Poliambulanza Hospital Institute, Brescia, 25121, Italy
| | | | - Barbara Chiavarina
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, University of Montpellier, Montpellier, France
| | - Andrei Turtoi
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, University of Montpellier, Montpellier, France
| | - Marco Presta
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Roberto Ronca
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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21
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Cho S, Joo B, Park M, Ahn SJ, Suh SH, Park YW, Ahn SS, Lee SK. A Radiomics-Based Model for Potentially More Accurate Identification of Subtypes of Breast Cancer Brain Metastases. Yonsei Med J 2023; 64:573-580. [PMID: 37634634 PMCID: PMC10462808 DOI: 10.3349/ymj.2023.0047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 06/06/2023] [Accepted: 06/20/2023] [Indexed: 08/29/2023] Open
Abstract
PURPOSE Breast cancer brain metastases (BCBM) may involve subtypes that differ from the primary breast cancer lesion. This study aimed to develop a radiomics-based model that utilizes preoperative brain MRI for multiclass classification of BCBM subtypes and to investigate whether the model offers better prediction accuracy than the assumption that primary lesions and their BCBMs would be of the same subtype (non-conversion model) in an external validation set. MATERIALS AND METHODS The training and external validation sets each comprised 51 cases (102 cases total). Four machine learning classifiers combined with three feature selection methods were trained on radiomic features and primary lesion subtypes for prediction of the following four subtypes: 1) hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-, 2) HR+/HER2+, 3) HR-/HER2+, and 4) triple-negative. After training, the performance of the radiomics-based model was compared to that of the non-conversion model in an external validation set using accuracy and F1-macro scores. RESULTS The rate of discrepant subtypes between primary lesions and their respective BCBMs were 25.5% (n=13 of 51) in the training set and 23.5% (n=12 of 51) in the external validation set. In the external validation set, the accuracy and F1-macro score of the radiomics-based model were significantly higher than those of the non-conversion model (0.902 vs. 0.765, p=0.004; 0.861 vs. 0.699, p=0.002). CONCLUSION Our radiomics-based model represents an incremental advance in the classification of BCBM subtypes, thereby facilitating a more appropriate personalized therapy.
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Affiliation(s)
- Seonghyeon Cho
- Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Bio Joo
- Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
| | - Mina Park
- Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Jun Ahn
- Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hyun Suh
- Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yae Won Park
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Image Data Science, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Soo Ahn
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Image Data Science, Yonsei University College of Medicine, Seoul, Korea
| | - Seung-Koo Lee
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Image Data Science, Yonsei University College of Medicine, Seoul, Korea
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22
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Lin L, Pfender K, Ditsch N, Kuhn C, Rahmeh M, Peng L, Schmoeckel E, Mayr D, Trillsch F, Mahner S, Kessler M, Jeschke U, Hester A. KLF11 is an independent negative prognostic factor for breast cancer from a cohort study and induces proliferation and inhibits apoptosis in vitro. Breast Cancer 2023; 30:758-771. [PMID: 37199905 PMCID: PMC10404175 DOI: 10.1007/s12282-023-01470-5] [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: 07/13/2022] [Accepted: 05/10/2023] [Indexed: 05/19/2023]
Abstract
BACKGROUND The therapy concepts that target several members of krüppel like factor (KLF) family have been achieved in breast cancer (BC). However, the role of KLF11 in BC remains unclear. This study explored the prognostic significance of KLF11 in BC patients and investigated its functional roles in this malignancy. METHODS Immunohistochemistry (IHC) staining of KLF11 in 298 patients' samples was performed to determine the prognostic role of the KLF11. Then the protein level was correlated to clinicopathological characteristics and survival outcomes. Afterward, the function of KLF11 was explored in vitro with siRNA-mediated loss-of-function of cell viability, proliferation, and apoptosis. RESULTS From the cohort study, we found that the expression of KLF11 was positively associated with highly proliferative BC of BC. Furthermore, prognostic analysis demonstrated that KLF11 was an independent negative factor for disease-free survival (DFS) and distant-metastasis-free survival (DMFS) of BC. The KLF11-related prognostic model for DFS and DMFS showed high accuracy in predicting the 3-,5- and 10 -year survival probability of BC patients. Additionally, the knockdown of KLF11 inhibited cell viability and proliferation, as well as induced cell apoptosis in MCF7 and MDA-MB-231 cells, while only inhibited cell viability and induced cell apoptosis in SK-BR-3 cells. CONCLUSIONS Our study indicated that targeting KLF11 is an interesting therapeutic concept and further research could lead to a new therapeutic improvement in BC, especially in highly aggressive molecular subtypes.
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Affiliation(s)
- Lili Lin
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Kristina Pfender
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Nina Ditsch
- Department of Gynecology and Obstetrics, University Hospital Augsburg, 86156, Augsburg, Germany
| | - Christina Kuhn
- Department of Gynecology and Obstetrics, University Hospital Augsburg, 86156, Augsburg, Germany
| | - Martina Rahmeh
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Lin Peng
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Elisa Schmoeckel
- Department of Pathology, Ludwig-Maximilians University of Munich, 81337, Munich, Germany
| | - Doris Mayr
- Department of Pathology, Ludwig-Maximilians University of Munich, 81337, Munich, Germany
| | - Fabian Trillsch
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Sven Mahner
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Mirjana Kessler
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Udo Jeschke
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.
- Department of Gynecology and Obstetrics, University Hospital Augsburg, 86156, Augsburg, Germany.
| | - Anna Hester
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
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23
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Sadasivam K, Manoharan JP, Palanisamy H, Vidyalakshmi S. The genomic landscape associated with resistance to aromatase inhibitors in breast cancer. Genomics Inform 2023; 21:e20. [PMID: 37415453 PMCID: PMC10326531 DOI: 10.5808/gi.23012] [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: 02/13/2023] [Revised: 05/12/2023] [Accepted: 05/17/2023] [Indexed: 07/08/2023] Open
Abstract
Aromatase inhibitors (AI) are drugs that are widely used in treating estrogen receptor (ER)-positive breast cancer patients. Drug resistance is a major obstacle to aromatase inhibition therapy. There are diverse reasons behind acquired AI resistance. This study aims at identifying the plausible cause of acquired AI resistance in patients administered with non-steroidal AIs (anastrozole and letrozole). We used genomic, transcriptomic, epigenetic, and mutation data of breast invasive carcinoma from The Cancer Genomic Atlas database. The data was then separated into sensitive and resistant sets based on patients' responsiveness to the non-steroidal AIs. A sensitive set of 150 patients and a resistant set of 172 patients were included for the study. These data were collectively analyzed to probe into the factors that might be responsible for AI resistance. We identified 17 differentially regulated genes (DEGs) among the two groups. Then, methylation, mutation, miRNA, copy number variation, and pathway analyses were performed for these DEGs. The top mutated genes (FGFR3, CDKN2A, RNF208, MAPK4, MAPK15, HSD3B1, CRYBB2, CDC20B, TP53TG5, and MAPK8IP3) were predicted. We also identified a key miRNA - hsa-mir-1264 regulating the expression of CDC20B. Pathway analysis revealed HSD3B1 to be involved in estrogen biosynthesis. This study reveals the involvement of key genes that might be associated with the development of AI resistance in ER-positive breast cancers and hence may act as a potential prognostic and diagnostic biomarker for these patients.
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Affiliation(s)
- Kirithika Sadasivam
- Department of Biotechnology, PSG College of Technology, Coimbatore 641004, Tamil Nadu, India
| | | | - Hema Palanisamy
- Department of Biotechnology, PSG College of Technology, Coimbatore 641004, Tamil Nadu, India
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24
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Fan R, Tao X, Zhai X, Zhu Y, Li Y, Chen Y, Dong D, Yang S, Lv L. Application of aptamer-drug delivery system in the therapy of breast cancer. Biomed Pharmacother 2023; 161:114444. [PMID: 36857912 DOI: 10.1016/j.biopha.2023.114444] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/05/2023] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
Despite significant treatment advances, breast cancer remains the leading cause of cancer death in women. From the current treatment situation, in addition to developing chemoresistant tumours, distant organ metastasis, and recurrences, patients with breast cancer often have a poor prognosis. Aptamers as "chemical antibodies" may be a way to resolve this dilemma. Aptamers are single-stranded, non-coding oligonucleotides (DNA or RNA), resulting their many advantages, including stability for long-term storage, simplicity of synthesis and function, and low immunogenicity, a high degree of specificity and antidote. Aptamers have gained popularity as a method for diagnosing and treating specific tumors in recent years. This article introduces the application of ten different aptamer delivery systems in the treatment and diagnosis of breast cancer, and systematically reviews their latest research progress in breast cancer treatment and diagnosis. It provides a new direction for the clinical treatment of breast cancer.
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Affiliation(s)
- Rui Fan
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xufeng Tao
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaohan Zhai
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yanna Zhu
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yunming Li
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yanwei Chen
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Deshi Dong
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shilei Yang
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Linlin Lv
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China.
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25
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Boccarelli A, Del Buono N, Esposito F. Cluster of resistance-inducing genes in MCF-7 cells by estrogen, insulin, methotrexate and tamoxifen extracted via NMF. Pathol Res Pract 2023; 242:154347. [PMID: 36738509 DOI: 10.1016/j.prp.2023.154347] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 02/03/2023]
Abstract
Breast cancer has become a leading cause of death for women as the economy has grown and the number of women in the labor force has increased. Several biomarkers with diagnostic, prognostic, and therapeutic implications for breast cancer have been identified in studies, leading to therapeutic advances. Resistance, on the other hand, is one of clinical practice's limitations. In this paper, we use Nonnegative Matrix Factorization to automatically extract two gene signatures from gene expression profiles of wild-type and resistance MCF-7 cells, which were then investigated further using pathways analysis and proved useful in relating resistance pathways to breast cancer regardless of the stimulus that caused it. A few extracted genes (including MAOA, IL4I1, RRM2, DUT, NME4, and SUMO3) represent new elements in the functional network for resistance in MCF-7 ER+ breast cancer. As a result of this research, a better understanding of how resistance occurs or the pathways that contribute to it may allow more effective therapies to be developed.
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Affiliation(s)
- Angelina Boccarelli
- Department of Precision and Regenerative Medicine and Polo Jonico, University of Bari Medical School, Piazza Giulio Cesare 11, Bari, Italy.
| | - Nicoletta Del Buono
- Department of Mathematics, University of Bari Aldo Moro, via Edoardo Orabona 4, 70125 Bari, Italy; INDAM-GNCS Research Group, Piazzale Aldo Moro, 5, 00185 Roma, Italy.
| | - Flavia Esposito
- Department of Mathematics, University of Bari Aldo Moro, via Edoardo Orabona 4, 70125 Bari, Italy; INDAM-GNCS Research Group, Piazzale Aldo Moro, 5, 00185 Roma, Italy.
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26
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Balalaeva IV, Krylova LV, Karpova MA, Shulga AA, Konovalova EV, Guryev EL, Deyev SM. Synergistic Effect of the Combined Action of Targeted and Photodynamic Therapy on HER2-Positive Breast Cancer. DOKL BIOCHEM BIOPHYS 2022; 507:330-333. [PMID: 36786996 DOI: 10.1134/s1607672922340038] [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: 10/10/2022] [Revised: 10/25/2022] [Accepted: 10/25/2022] [Indexed: 02/15/2023]
Abstract
Development of combined schemes for the treatment of oncological diseases is a promising strategy to improve the effectiveness of antitumor therapy. This paper shows the fundamental possibility of multiplying the antitumor effect by combining targeted and photodynamic therapy. It was demonstrated that sequential treatment of HER-2 positive breast cancer cells with the targeted toxin DARPin-LoPE and the photoactive compound photodithazine leads to a synergistic enhancement of their effect. In the future, this approach is intended to achieve the maximum therapeutic effect while minimizing the risks of negative side effects.
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Affiliation(s)
- I V Balalaeva
- Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia.
| | - L V Krylova
- Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - M A Karpova
- Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - A A Shulga
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - E V Konovalova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - E L Guryev
- Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - S M Deyev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. .,Sechenov First Moscow State Medical University, Moscow, Russia.
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27
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Dabi Y, Bendifallah S, Suisse S, Haury J, Touboul C, Puchar A, Favier A, Daraï E. Overview of non-coding RNAs in breast cancers. Transl Oncol 2022; 25:101512. [PMID: 35961269 PMCID: PMC9382556 DOI: 10.1016/j.tranon.2022.101512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/18/2022] [Accepted: 08/02/2022] [Indexed: 12/24/2022] Open
Abstract
Breast cancer in women is the second most common cancer and the fifth leading cause of cancer death worldwide. Although earlier diagnosis and detection of breast cancer has resulted in lower mortality rates, further advances in prevention, detection, and treatment are needed to improve outcomes and survival for women with breast cancer as well as to offer a personalized therapeutic approach. It is now well-established that non-coding RNAs (ncRNAs) represent 98% of the transcriptome but in-depth knowledge about their involvement in the regulation of gene expression is lacking. A growing body of research indicates that ncRNAs are essential for tumorigenesis by regulating the expression of tumour-related genes. In this review, we focus on their implication in breast cancer genesis but also report the latest knowledge of their theragnostic and therapeutic role. We highlight the need for accurate quantification of circulating ncRNAs which is determinant to develop reliable biomarkers. Further studies are mandatory to finally enter the era of personalized medicine for women with breast cancer.
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Affiliation(s)
- Yohann Dabi
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris; Clinical Research Group (GRC) Paris 6: Centre Expert Endométriose (C3E), Sorbonne University (GRC6 C3E SU); INSERM UMR_S_938, Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Sorbonne University, Paris 75020, France.
| | - Sofiane Bendifallah
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris; Clinical Research Group (GRC) Paris 6: Centre Expert Endométriose (C3E), Sorbonne University (GRC6 C3E SU); INSERM UMR_S_938, Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Sorbonne University, Paris 75020, France
| | | | - Julie Haury
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris
| | - Cyril Touboul
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris; Clinical Research Group (GRC) Paris 6: Centre Expert Endométriose (C3E), Sorbonne University (GRC6 C3E SU); INSERM UMR_S_938, Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Sorbonne University, Paris 75020, France
| | - Anne Puchar
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris
| | - Amélia Favier
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris
| | - Emile Daraï
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris; Clinical Research Group (GRC) Paris 6: Centre Expert Endométriose (C3E), Sorbonne University (GRC6 C3E SU); INSERM UMR_S_938, Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Sorbonne University, Paris 75020, France
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Bazzazan S, Moeinabadi-Bidgoli K, Lalami ZA, Bazzazan S, Mehrarya M, Yeganeh FE, Hejabi F, Akbarzadeh I, Noorbazargan H, Jahanbakhshi M, Hossein-khannazer N, Mostafavi E. Engineered UIO-66 metal-organic framework for delivery of curcumin against breast cancer cells: An in vitro evaluation. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.104009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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29
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Phytotherapeutic applications of alkaloids in treating breast cancer. Biomed Pharmacother 2022; 155:113760. [DOI: 10.1016/j.biopha.2022.113760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 09/12/2022] [Accepted: 09/26/2022] [Indexed: 11/23/2022] Open
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30
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Xu S, Sun X, Luo L, Yang Y, Guo Q, Tang S, Jiang Z, Li Y, Han J, Gan W, Yang F, Zhang X, Liu Y, Sun C, He J, Liu M, Zuo D, Zhu W, Wu Y. XS-2, a novel potent dual PI3K/mTOR inhibitor, exhibits high in vitro and in vivo anti-breast cancer activity and low toxicity with the potential to inhibit the invasion and migration of triple-negative breast cancer. Biomed Pharmacother 2022; 155:113537. [PMID: 36113258 DOI: 10.1016/j.biopha.2022.113537] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 11/02/2022] Open
Abstract
Breast cancer has become the most commonly diagnosed cancer, surpassing lung cancer, with 2.26 million new breast cancers worldwide in 2020. Hence, there is an urgent need to develop effective molecularly targeted therapeutic drugs to treat breast cancer. In this paper, we designed, synthesized and screened a novel thiophene-triazine derivative, XS-2, as a potent dual PI3K/mTOR inhibitor for the treatment of breast cancer. Also, XS-2 was found to be potentially effective against triple-negative breast cancer (TNBC) in vitro during the investigation. We evaluated the in vitro inhibitory effect of XS-2 on 10 cancer cell lines by MTT and 6 kinases to investigated its in vivo antitumor activity in MCF-7 xenograft tumor-bearing BALB/c nude mice. In addition, the in vitro/in vivo toxicity to mice was also assessed by hemolytic toxicity, H&E staining and blood biochemical analysis. In order to investigate the antitumor mechanism of XS-2, a series of experiments were carried out in vitro/in vivo animal model and molecular biological levels such as the cell cycle and the apoptosis assay, real-time PCR, western blot, docking and molecular simulations analysis, etc. What's more, wound healing assay, Transwell and Western Blot were applied to explore the ability of XS-2 to inhibit the cell invasion and migration. The results showed that XS-2 exhibited strong antitumor activity both in vitro and in vivo. The inhibitory activities of XS-2 on ten cancer cell lines were ranging from 1.07 ± 0.11 to 0.002 ± 0.001 μM, which were 1565 times better than that of the lead compound GDC-0941, inhibitory activities against PI3Kα and mTOR kinases were 291.0 and 60.8 nM, respectively. Notably, XS-2 not only showed significant in vivo antitumor activity and low toxicity, with the tumor inhibition rate of 57.0 %, but also exhibited strong inhibitory in the expression of related proteins of PI3K pathway in tumor tissues. In addition, XS-2 significantly inhibited breast cancer MCF-7 and MDA-MB-231 cells in a concentration- and time-dependent manner, and inhibited the migration and invasion ability of MDA-MB-231 and MCF-7 cells. More than that, XS-2 could inhibit the increase of the expression levels of N-cadherin and vimentin upregulated by EGF and reversed the E-cadherin expression down regulated by EGF, resulting in inhibiting EMT in MCF-7 and MDA-MB-231 cells. The results showed that XS-2 was expected to be successfully developed as a high-efficiency and low-toxicity breast cancer therapeutic drug with the potential to inhibit the invasion and migration of TNBC. This provides a new research idea for the treatment of TNBC, which is of great significance.
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Affiliation(s)
- Shan Xu
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Xin Sun
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Leixuan Luo
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Yang Yang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Qiuyan Guo
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Sheng Tang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Zhiyan Jiang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Yuzhen Li
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Jiaqian Han
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Wenhui Gan
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Feiyi Yang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Xuan Zhang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Yijun Liu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Chuanchuan Sun
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Jie He
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Meng Liu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China
| | - Daiying Zuo
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
| | - Wufu Zhu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China.
| | - Yingliang Wu
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
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Yip HF, Chowdhury D, Wang K, Liu Y, Gao Y, Lan L, Zheng C, Guan D, Lam KF, Zhu H, Tai X, Lu A. ReDisX, a machine learning approach, rationalizes rheumatoid arthritis and coronary artery disease patients uniquely upon identifying subpopulation differentiation markers from their genomic data. Front Med (Lausanne) 2022; 9:931860. [PMID: 36072953 PMCID: PMC9441882 DOI: 10.3389/fmed.2022.931860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 07/28/2022] [Indexed: 11/29/2022] Open
Abstract
Diseases originate at the molecular-genetic layer, manifest through altered biochemical homeostasis, and develop symptoms later. Hence, symptomatic diagnosis is inadequate to explain the underlying molecular-genetic abnormality and individual genomic disparities. The current trends include molecular-genetic information relying on algorithms to recognize the disease subtypes through gene expressions. Despite their disposition toward disease-specific heterogeneity and cross-disease homogeneity, a gap still exists in describing the extent of homogeneity within the heterogeneous subpopulation of different diseases. They are limited to obtaining the holistic sense of the whole genome-based diagnosis resulting in inaccurate diagnosis and subsequent management. Addressing those ambiguities, our proposed framework, ReDisX, introduces a unique classification system for the patients based on their genomic signatures. In this study, it is a scalable machine learning algorithm deployed to re-categorize the patients with rheumatoid arthritis and coronary artery disease. It reveals heterogeneous subpopulations within a disease and homogenous subpopulations across different diseases. Besides, it identifies granzyme B (GZMB) as a subpopulation-differentiation marker that plausibly serves as a prominent indicator for GZMB-targeted drug repurposing. The ReDisX framework offers a novel strategy to redefine disease diagnosis through characterizing personalized genomic signatures. It may rejuvenate the landscape of precision and personalized diagnosis and a clue to drug repurposing.
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Affiliation(s)
- Hiu F. Yip
- Computational Medicine Laboratory, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Department of Mathematics, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Debajyoti Chowdhury
- Computational Medicine Laboratory, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Kexin Wang
- National Key Clinical Specialty, Engineering Technology Research Center of Education Ministry of China, Guangzhou, China
- Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Neurosurgery Institute, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yujie Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yao Gao
- Department of Psychiatry, First Hospital, First Clinical Medical College of Shanxi Medical University, Taiyuan, China
| | - Liang Lan
- Department of Communication Studies, School of Communication, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Chaochao Zheng
- Department of Mathematics, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Daogang Guan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, China
| | - Kei F. Lam
- Department of Mathematics, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Hailong Zhu
- Computational Medicine Laboratory, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Xuecheng Tai
- Department of Mathematics, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Aiping Lu
- Computational Medicine Laboratory, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
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32
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Zhang Z, Wang X, Wang Y, Zhou D, Wu H, Cheng W, Wang Q, Zheng G, Wang J, Gu J. Effect of long noncoding RNA CCAT2 on drug sensitivity to 5-fluorouracil of breast cancer cells through microRNA-145 meditated by p53. J Biochem Mol Toxicol 2022; 36:e23176. [PMID: 35968984 DOI: 10.1002/jbt.23176] [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: 09/01/2021] [Revised: 06/02/2022] [Accepted: 07/21/2022] [Indexed: 11/09/2022]
Abstract
The current study was set out to investigate the mechanism by which silenced long noncoding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2) modulates the cell growth, migration, invasion, and drug sensitivity of breast cancer (BC) cells to 5-fluorouracil (5-Fu) with the involvement of miR-145 and p53. First, high CCAT2 expression was presented in BC cells and tissues. Subsequently, the links between CCAT2 expression and BC clinicopathological features were analyzed. Highly-expressed CCAT2 was linked to lymph node metastasis, positive progesterone receptor, estrogen receptor, and Ki-67 of BC cells. Then, the gain- and loss-of-function approaches were performed to measure the regulatory role of CCAT2 in the biological processes of BC cells. Silencing of CCAT2 suppressed in vitro cell growth, proliferation, invasion, migration abilities, and epithelial-mesenchymal transformation, increased cell apoptosis, and enhanced drug sensitivity of BC cells. Silencing of CCAT2 upregulated miR-145, which was poorly expressed in drug-resistant BC cells. p53 can bind to the miR-145 promoter region and increase miR-145 expression. Upregulation of miR-145 induced by silencing of CCAT2 can be invalidated by p53-siRNA. To conclude, p53-induced activation of miR-145 could be inhibited by CCAT2, while overexpression of CCAT2 could improve the drug resistance of BC cells to 5-Fu.
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Affiliation(s)
- Ziyun Zhang
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Xuedong Wang
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Yueping Wang
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China.,Department of Molecular and Cellular Biology, University of Connecticut, Storrs, Connecticut, USA
| | - Daoping Zhou
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Huaiguo Wu
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Wei Cheng
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Qingping Wang
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Guopei Zheng
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Ji Wang
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Juan Gu
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China.,Department of Pathology, The Fifth People's Hospital of Wuxi, Nanjing Medical University, Wuxi, Jiangsu, China
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33
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Chung WP, Huang WL, Lee CH, Hsu HP, Huang WL, Liu YY, Su WC. PI3K inhibitors in trastuzumab-resistant HER2-positive breast cancer cells with PI3K pathway alterations. Am J Cancer Res 2022; 12:3067-3082. [PMID: 35968355 PMCID: PMC9360227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/08/2022] [Indexed: 06/15/2023] Open
Abstract
The activation of the PI3K signaling pathway resulting from genetic alterations induces carcinogenesis and resistance to anticancer therapies. Breast cancer is a major malignancy that is associated with dysregulation of the PI3K signaling pathway. PIK3CA mutations and PTEN loss occur in every subtype of breast cancer. PI3K inhibitors are being evaluated in breast cancer after the success of an alpha isoform-specific PI3K inhibitor in estrogen receptor (ER)-positive/HER2-negative metastatic breast cancer. Some preclinical data indicate the potential for PI3K/mTOR targeting in combination with trastuzumab for HER2-positive breast cancer with or without expression of the estrogen receptor. However, the role of this therapy in HER2-positive breast cancer with PIK3CA mutations and/or PTEN loss remains unclear. We examined three HER2-positive, ER-negative breast cancer cell lines to determine the efficacy of a novel alpha isoform-specific PI3K inhibitor in combination with trastuzumab. The results indicated that this combination was effective in PIK3CA-mutant or PTEN-deficient breast cancer cells by inducing apoptosis and inhibiting the expression of downstream proteins. PTEN loss by siRNA modulation in parental HER2-positive cancer cells with PI3K signaling pathway alterations could not confer resistance to alpelisib or GDC-0077 plus trastuzumab. We selected the CK-MB-1 cell line without alterations in the PI3K pathway to demonstrate that PI3K inhibitors plus trastuzumab represented a biomarker-specific treatment. In vivo effects of alpelisib plus trastuzumab were tested and confirmed in a mouse model, showing the combination strategy offered the best opportunity to achieve tumor volume reduction. With known safety profiles, this cytotoxic chemotherapy-free regimen warrants further attention as a biomarker-driven strategy for treating HER2-positive breast cancer.
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Affiliation(s)
- Wei-Pang Chung
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung UniversityTainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
| | - Wei-Lun Huang
- Center of Applied Nanomedicine, National Cheng Kung UniversityTainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
| | - Chun-Hui Lee
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung UniversityTainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
| | - Hui-Ping Hsu
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
| | - Wan-Ling Huang
- Center of Applied Nanomedicine, National Cheng Kung UniversityTainan, Taiwan
| | - You-Yu Liu
- Center of Applied Nanomedicine, National Cheng Kung UniversityTainan, Taiwan
- Institute of Basic Medical Science, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
| | - Wu-Chou Su
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung UniversityTainan, Taiwan
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Population Pharmacokinetics of Palbociclib and Its Correlation with Clinical Efficacy and Safety in Patients with Advanced Breast Cancer. Pharmaceutics 2022; 14:pharmaceutics14071317. [PMID: 35890213 PMCID: PMC9322950 DOI: 10.3390/pharmaceutics14071317] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/03/2022] [Accepted: 06/10/2022] [Indexed: 12/04/2022] Open
Abstract
Neutropenia is the most frequent dose-limiting toxicity reported in patients with metastatic breast cancer receiving palbociclib. The objective of this study was to investigate the pharmacokinetic–pharmacodynamic (PK/PD) relationships for toxicity (i.e., absolute neutrophil count, ANC) and efficacy (i.e., progression-free survival, PFS). A semi-mechanistic PK/PD model was used to predict neutrophils’ time course using a population approach (NONMEM). Influence of demographic and clinical characteristics was evaluated. Cox proportional hazards models were developed to evaluate the influence of palbociclib PK on PFS. A two-compartment model with first-order absorption and a lag time adequately described the 255 palbociclib concentrations provided by 44 patients. The effect of the co-administration of proton-pump inhibitors in fasting conditions increased palbociclib clearance by 56%. None of the tested covariates affected the PD parameters. Model-based simulations confirmed the concentration-dependent and non-cumulative properties of palbociclib-induced neutropenia, reversible after treatment withdrawal. The ANC nadir occurred approximately at day 24 of each cycle. Cox analyses revealed a trend for better PFS with increasing palbociclib exposure in older patients. By characterizing palbociclib-induced neutropenia, this model offers support to clinicians to rationally optimize treatment management through patient-individualized strategies.
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Breast Cancer Metastasis: Mechanisms and Therapeutic Implications. Int J Mol Sci 2022; 23:ijms23126806. [PMID: 35743249 PMCID: PMC9224686 DOI: 10.3390/ijms23126806] [Citation(s) in RCA: 167] [Impact Index Per Article: 55.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/15/2022] [Accepted: 06/17/2022] [Indexed: 02/05/2023] Open
Abstract
Breast cancer is the most common malignancy in women worldwide. Metastasis is the leading cause of high mortality in most cancers. Although predicting the early stage of breast cancer before metastasis can increase the survival rate, breast cancer is often discovered or diagnosed after metastasis has occurred. In general, breast cancer has a poor prognosis because it starts as a local disease and can spread to lymph nodes or distant organs, contributing to a significant impediment in breast cancer treatment. Metastatic breast cancer cells acquire aggressive characteristics from the tumor microenvironment (TME) through several mechanisms including epithelial–mesenchymal transition (EMT) and epigenetic regulation. Therefore, understanding the nature and mechanism of breast cancer metastasis can facilitate the development of targeted therapeutics focused on metastasis. This review discusses the mechanisms leading to metastasis and the current therapies to improve the early diagnosis and prognosis in patients with metastatic breast cancer.
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36
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Zuo Q, Park NH, Lee JK, Madak Erdogan Z. Liver Metastatic Breast Cancer: Epidemiology, Dietary Interventions, and Related Metabolism. Nutrients 2022; 14:2376. [PMID: 35745105 PMCID: PMC9228756 DOI: 10.3390/nu14122376] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/22/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
The median overall survival of patients with metastatic breast cancer is only 2-3 years, and for patients with untreated liver metastasis, it is as short as 4-8 months. Improving the survival of women with breast cancer requires more effective anti-cancer strategies, especially for metastatic disease. Nutrients can influence tumor microenvironments, and cancer metabolism can be manipulated via a dietary modification to enhance anti-cancer strategies. Yet, there are no standard evidence-based recommendations for diet therapies before or during cancer treatment, and few studies provide definitive data that certain diets can mediate tumor progression or therapeutic effectiveness in human cancer. This review focuses on metastatic breast cancer, in particular liver metastatic forms, and recent studies on the impact of diets on disease progression and treatment.
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Affiliation(s)
- Qianying Zuo
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (Q.Z.); (N.H.P.)
| | - Nicole Hwajin Park
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (Q.Z.); (N.H.P.)
| | - Jenna Kathryn Lee
- Department of Neuroscience, Northwestern University, Evanston, IL 60208, USA;
| | - Zeynep Madak Erdogan
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (Q.Z.); (N.H.P.)
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Carl R. Woese Institute of Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Biomedical and Translational Sciences, Carle-Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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37
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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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Sadoughi F, Dana PM, Homayoonfal M, Sharifi M, Asemi Z. Molecular basis of melatonin protective effects in metastasis: A novel target of melatonin. Biochimie 2022; 202:15-25. [DOI: 10.1016/j.biochi.2022.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 05/19/2022] [Accepted: 05/19/2022] [Indexed: 11/16/2022]
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Du C, Wang T, Jia J, Li J, Xiao Y, Wang J, Mao P, Wang N, Shi L, Wang M. Suppression of RPL34 Inhibits Tumor Cell Proliferation and Promotes Apoptosis in Glioblastoma. Appl Biochem Biotechnol 2022; 194:3494-3506. [PMID: 35377127 DOI: 10.1007/s12010-022-03857-0] [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: 09/24/2021] [Accepted: 02/24/2022] [Indexed: 11/30/2022]
Abstract
Accumulating evidence indicates Ribosomal protein 34 (RPL34) promotes tumor malignance and its expression is associated with poor prognosis in multiple cancer cells. However, the physiological role and biological mechanism of RPL34 in glioblastoma (GBM) remain unclear. Hence, this study aimed to investigate the expression and the role of RPL34 in GBM. A total of 59 glioma samples and 12 normal brains for epilepsy surgery were used to determine the underlying mechanisms and the biological behaviors of RPL34 in GBM. In this study, we identified that RPL34 expression was significantly (p < 0.05) enriched in GBM tumors compared with low-grade glioma and normal brain, and its expression was associated with poor survival. Additionally, RPL34 was functionally required for tumor proliferation in vitro. Mechanically, inhibition of RPL34 induced glioma cell apoptosis by activation of Bad/Caspase7/PARP signaling pathway. The RPL34 promotes cell survival in GBM and could be a potential therapeutic target for GBM.
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Affiliation(s)
- Changwang Du
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Taoning Wang
- Department of Neurosurgery, Ningxian Second People's Hospital, Qing'Yang, 745201, Gansu Province, China
| | - Jinning Jia
- Department of Neurosurgery, Ningxian Second People's Hospital, Qing'Yang, 745201, Gansu Province, China
| | - Junjun Li
- Department of Radiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Yi Xiao
- Department of Ultrasonography, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Jia Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
- Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an , 710061, Shaanxi Province, China
| | - Ping Mao
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Ning Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Luoning Shi
- Department of Kidney Transplantation, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
| | - Maode Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
- Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an , 710061, Shaanxi Province, China.
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40
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Chung WP, Huang WL, Liao WA, Hung CH, Chiang CW, Cheung CHA, Su WC. FTY720 in resistant human epidermal growth factor receptor 2-positive breast cancer. Sci Rep 2022; 12:241. [PMID: 34997132 PMCID: PMC8742024 DOI: 10.1038/s41598-021-04328-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/21/2021] [Indexed: 12/29/2022] Open
Abstract
The prognosis of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has considerably improved. However, no reliable treatment besides anti-HER2 strategies has been available. FTY720, a small-molecule compound used for treating refractory multiple sclerosis, has been reported to have beneficial effects against cancers. We therefore evaluated the efficacy of FTY720 in trastuzumab-resistant breast cancer cells and investigated the possible mechanism involved. This study evaluated morphological changes after FTY720 treatment. Antiproliferative WST-1 assays and LDH Cytotoxicity Assay Kits were used to determine the treatment effects of drugs, whereas Western blot analysis was used to evaluate protein expression. Apoptotic events were investigated through annexin V staining and TUNEL assays using flow cytometry. FTY720 was effective in trastuzumab-resistant breast cancer cell lines despite the presence of PIK3CA mutation. Studied on a xenograft mouse model, FTY720-treated groups had statistically significantly poorer HCC1954 xenograft growth in vivo compared with the control group. Our findings suggest that FTY720 can overcome resistance to trastuzumab therapy in patients with HER2-positive breast cancer, with FTY720 plus trastuzumab might offer even better efficacy in vitro and in vivo.
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Affiliation(s)
- Wei-Pang Chung
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Lun Huang
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan.,Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-An Liao
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-Hua Hung
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Wu Chiang
- Institute of Molecular Medicine, College of Medicine and Center for Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
| | - Chun Hei Antonio Cheung
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. .,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Wu-Chou Su
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. .,Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan.
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Integration of Genomic Profiling and Organoid Development in Precision Oncology. Int J Mol Sci 2021; 23:ijms23010216. [PMID: 35008642 PMCID: PMC8745679 DOI: 10.3390/ijms23010216] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 11/26/2022] Open
Abstract
Precision oncology involves an innovative personalized treatment strategy for each cancer patient that provides strategies and options for cancer treatment. Currently, personalized cancer medicine is primarily based on molecular matching. Next-generation sequencing and related technologies, such as single-cell whole-transcriptome sequencing, enable the accurate elucidation of the genetic landscape in individual cancer patients and consequently provide clinical benefits. Furthermore, advances in cancer organoid models that represent genetic variations and mutations in individual cancer patients have direct and important clinical implications in precision oncology. This review aimed to discuss recent advances, clinical potential, and limitations of genomic profiling and the use of organoids in breast and ovarian cancer. We also discuss the integration of genomic profiling and organoid models for applications in cancer precision medicine.
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Pyroptosis-Related Gene Signature Is a Novel Prognostic Biomarker for Sarcoma Patients. DISEASE MARKERS 2021; 2021:9919842. [PMID: 34904022 PMCID: PMC8665299 DOI: 10.1155/2021/9919842] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/07/2021] [Accepted: 11/13/2021] [Indexed: 01/01/2023]
Abstract
Sarcoma is a rare and an extremely aggressive form of cancer that originates from mesenchymal cells. Pyroptosis exerts a dual effect on tumours by inhibiting tumour cell proliferation while creating a microenvironment suitable for tumour cell development and proliferation. However, the significance of pyroptosis-related gene (PRG) expression in sarcoma has not yet been evaluated. Here, we conduct a retrospective analysis to examine PRG expression in 256 sarcoma samples from The Cancer Genome Atlas database. We identified the PRGs that had a significant correlation with overall patient survival in sarcoma by performing a univariate Cox regression analysis. Subsequently, we conducted a LASSO regression analysis and created a risk model for a six-PRG signature. As indicated from the Kaplan–Meier analysis, this signature revealed a significant difference between high- and low-risk sarcoma patients. A receiver operating characteristic curve analysis confirmed that this signature could predict overall patient survival in sarcoma patients with high sensitivity and specificity. Gene ontology annotation and Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analyses revealed that five independent PRGs were closely associated with increased immune activity. Moreover, we also deciphered that increased number of immune cells infiltrated the tumour microenvironment in sarcoma. In brief, the PRG signature can effectively act as novel prognostic biomarker for sarcoma patients and is associated with the tumour immune microenvironment.
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Hegde M, Bhat SM, Guruprasad KP, Moka R, Ramachandra L, Satyamoorthy K, Joshi MB. Human breast tumor derived endothelial cells exhibit distinct biological properties. Biol Cell 2021; 114:73-85. [PMID: 34755911 DOI: 10.1111/boc.202100015] [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: 03/18/2021] [Revised: 09/28/2021] [Accepted: 10/18/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND INFORMATION Excessive angiogenesis characterized by leaky, tortuous, and chaotic vasculature is one of the hallmarks of cancers and is significantly correlated to poor prognosis. Disorganized angiogenesis leads to poor perfusion of anti-cancer drugs and limits access to immune cells. Hence, impeding angiogenesis is one of the attractive therapeutic targets to inhibit progression and metastasis in several solid tumors including breast. RESULTS We have developed a robust and reproducible method for isolating and ex vivo culture of endothelial cells (EC) derived from non-malignant (Endo-N) and malignant (Endo-T) part from clinically characterized human breast tumors. RT-PCR and immunoblotting analysis indicated that these cells exhibited expression of endothelial specific genes such as PECAM-1 (CD31), Endoglin (CD105), eNOS, VE-cadherin, VCAM1, and MCAM. Vasculogenic mimicry and contamination of progenitor EC recruited in tumors was ruled out by absence of CD133 expression and normal karyotype. Both the cell types showed stable expression of CD31 and CD105 up to seven passages. Furthermore, compared to Endo-N cells, Endo-T cells showed (a) constitutively increased proliferation marked by nearly 36% of cells in mitotic phase, (b) requirement of glutamine for cell survival, (c) pro-migratory phenotype, (d) produced increased number of sprouts in 3D cultures, and (e) resistance to sorafenib. CONCLUSION Tumor derived EC showed distinct biological properties compared to normal breast EC. SIGNIFICANCE Our method for isolating endothelial cell types from human breast tumors may be explored to (a) understand cellular and molecular mechanisms, (b) screen anti-angiogenic molecules, and (c) formulate organoid cultures to develop personalized medicine facilitating better clinical management of breast cancers.
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Affiliation(s)
- Mangala Hegde
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Sharath Mohan Bhat
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Kanive Parashiva Guruprasad
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Rajasekhar Moka
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Lingadakai Ramachandra
- Department of Surgery, Kasturba Hospital, Manipal Academy of Higher Education, Manipal, India
| | - Kapaettu Satyamoorthy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Manjunath B Joshi
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
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Yetkin D, Balli E, Ayaz F. Antiproliferative activity of Tamoxifen, Vitamin D3 and their concomitant treatment. EXCLI JOURNAL 2021; 20:1394-1406. [PMID: 34737683 PMCID: PMC8564918 DOI: 10.17179/excli2021-3989] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/24/2021] [Indexed: 11/10/2022]
Abstract
Breast cancer stands out as the most common cancer type among women throughout the world. Especially for the estrogen receptor alpha (ER α +) positive breast cancer cells Tamoxifen has been widely used as an anti-cancer agent. Tamoxifen's mechanism of action is through ER. It binds to the receptor and leads to a conformational change which eventually prevents cancer cells proliferation and survival. In our current study, we aimed to investigate the combination of Tamoxifen with Vitamin D3 to test whether this combination will enhance the anti-cancer effect of Tamoxifen on breast cancer cells in vitro. Vitamin D3 has sterol structure and this property enables it to act similar to hormones. Vitamin D Receptor (VDR) has been commonly found in different types of cancer cells including but not limited to breast and prostate cancer cells. Through this receptor Vitamin D3 acts as an anti-proliferative agent. We examined the proliferation rate, apoptosis and necrosis levels as well as cell cycle progression in MCF-7 breast cancer cell line in the presence of Vitamin D3 and Tamoxifen to compare the changes with the Tamoxifen treated group. Our results suggest that Tamoxifen was a more potent anti-cancer agent than Vitamin D3 or its combination with Vitamin D3 based on cell cycle arrest, apoptosis and cell proliferation levels. This effect in the apoptosis rate and cell cycle stage of the MCF-7 cells were in line with the changes in gene expression profile of P53, BAX and BCL-2. Our results suggest that Tamoxifen by itself is adequate enough and more potent than Vitamin D3 or its combination with Vitamin D3 as anti-cancer agent for the breast cancer cells in vitro.
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Affiliation(s)
- Derya Yetkin
- Mersin University, Advanced Technology Education Research and Application Center, 33110, Mersin, Turkey
| | - Ebru Balli
- Mersin University, Department of Histology and Embryology, 33110 Mersin, Turkey
| | - Furkan Ayaz
- Mersin University, Department of Biotechnology, Faculty of Arts and Science, 33110, Mersin, Turkey
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Agarwal S, Sau S, Iyer AK, Dixit A, Kashaw SK. Multiple strategies for the treatment of invasive breast carcinoma: A comprehensive prospective. Drug Discov Today 2021; 27:585-611. [PMID: 34715356 DOI: 10.1016/j.drudis.2021.10.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 08/10/2021] [Accepted: 10/19/2021] [Indexed: 01/22/2023]
Abstract
In this review, we emphasize on evolving therapeutic strategies and advances in the treatment of breast cancer (BC). This includes small-molecule inhibitors under preclinical and clinical investigation, phytoconstituents with antiproliferative potential, targeted therapies as antibodies and antibody-drug conjugates (ADCs), vaccines as immunotherapeutic agents and peptides as a novel approach inhibiting the interaction of oncogenic proteins. We provide an update of molecules under different phases of clinical investigation which aid in the identification of loopholes or shortcomings that can be overcomed with future breast cancer research.
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Affiliation(s)
- Shivangi Agarwal
- Department of Pharmaceutical Sciences, Dr Harisingh Gour University, Sagar, MP, India
| | - Samaresh Sau
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA; Molecular Imaging Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | | | - Sushil K Kashaw
- Department of Pharmaceutical Sciences, Dr Harisingh Gour University, Sagar, MP, India.
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Soltaninasab S, Ahmadzadeh M, Shahhosseini S, Mohit E. Evaluating the efficacy of immobilized metal affinity chromatography (IMAC) for host cell protein (HCP) removal from anti-HER2 scFv expressed in Escherichia coli. Protein Expr Purif 2021; 190:106004. [PMID: 34688918 DOI: 10.1016/j.pep.2021.106004] [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: 09/14/2021] [Revised: 10/17/2021] [Accepted: 10/19/2021] [Indexed: 12/24/2022]
Abstract
Host cell proteins (HCPs) are process-related impurities that have influence on product safety and efficacy. HCPs should effectively be removed by chromatographic steps in downstream purification process. In this study, we aimed to evaluate the efficacy of immobilized-metal affinity chromatography (IMAC) for separation of HCPs from anti-HER2 single chain fragment variable (scFv) expressed in E. coli. This study explored how different purification conditions including native, denaturing and hybrid affect HCP level in purified anti-HER2 scFv. Furthermore, the effects of NaCl concentration in wash buffer as well as imidazole concentration in wash and elution buffer on purification yield and HCP level in purified anti-HER2 scFv were evaluated. It was found that increasing imidazole concentration in wash and elution buffers in native conditions reduced the yield of anti-HER2 scFv purification. However, enhancing NaCl concentration in wash buffer in purification under native conditions led to significant increase in the amount of anti-HER2 scFv without any change in protein purity. Herein, none of the IMAC purification methods conducted on soluble cytoplasmic proteins under native conditions could reduce the amount of HCP to acceptable level. HCP content was only lowered to ˂ 10 ppm when inclusion bodies were purified under hybrid conditions. Furthermore, increasing imidazole concentration in wash buffer in purification under hybrid conditions led to significant increase in eluted anti-HER2 scFv concentration, while HCP content was also increased in this condition. Overall, purification under hybrid conditions using wash buffer containing 40 mM imidazole resulted in the highest yield and acceptable level of HCP.
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Affiliation(s)
- Saba Soltaninasab
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Ahmadzadeh
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soraya Shahhosseini
- School of Pharmacy, Pharmaceutical Chemistry and Radiopharmacy Department and Protein Technology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elham Mohit
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Fujikawa T, Sanada F, Taniyama Y, Shibata K, Katsuragi N, Koibuchi N, Akazawa K, Kanemoto Y, Kuroyanagi H, Shimazu K, Rakugi H, Morishita R. Periostin Exon-21 Antibody Neutralization of Triple-Negative Breast Cancer Cell-Derived Periostin Regulates Tumor-Associated Macrophage Polarization and Angiogenesis. Cancers (Basel) 2021; 13:cancers13205072. [PMID: 34680221 PMCID: PMC8533925 DOI: 10.3390/cancers13205072] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/22/2021] [Accepted: 10/04/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary Despite remarkable advances in breast cancer treatment, few strategies other than standard cytotoxic chemotherapy are available for patients with triple-negative breast cancer (TNBC) due to the lack of therapeutic target molecules. TNBC is still the most aggressive subtype, with a high risk of recurrence and metastasis within 2 years after initial treatment. Thus, there is an unmet medical need to develop new treatments for metastatic and recurrent TNBC patients. In this study we tested a new antibody, targeting extracellular periostin protein alternative splicing variants, which are induced by conventional chemotherapy or during the process of endothelial mesenchymal transition. This antibody reduced periostin-secreting TNBC in a mouse xenograft model, accompanied by a decrease in the number of M2 tumor-associated macrophages and tumor vessels. Periostin alternative splicing variants might be a specific and safe therapeutic target in patients with TNBC. Abstract Periostin (Pn) is involved in multiple processes of cancer progression. Previously, we reported that Pn expression is correlated with mesenchymal tumor markers and poor prognosis in triple-negative breast cancer (TNBC). In the TNBC xenograft model, chemotherapy increased expression of a Pn alternative splicing variant (ASV) with exon 21, and administration of the neutralizing antibody against Pn with exon 21 (Pn-21 Ab) overcame chemoresistance with a reduction in the mesenchymal cancer cell fraction. In the present study, the role of Pn ASV with exon 21 in TNBC progression has been addressed. We first established a stable cell line carrying a fluorescence-based splicing reporter. Pn-positive TNBC has higher expression of genes related to tumor-associated macrophage (TAM) recruitment and ECM-receptor interaction than Pn-negative cells. In a xenograft model, only Pn-positive cells initiated tumor formation, and the Pn-21 Ab suppressed tumor cell growth, accompanied by decreased M2 TAM polarization and the number of tumor vessels. These data suggest that cancer cell-derived Pn ASV educates TAMs and regulates angiogenesis, which in turn establishes a microenvironmental niche that is supportive of TNBC.
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Affiliation(s)
- Tatsuya Fujikawa
- Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (T.F.); (F.S.); (Y.T.); (K.S.); (N.K.); (N.K.)
| | - Fumihiro Sanada
- Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (T.F.); (F.S.); (Y.T.); (K.S.); (N.K.); (N.K.)
| | - Yoshiaki Taniyama
- Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (T.F.); (F.S.); (Y.T.); (K.S.); (N.K.); (N.K.)
- Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
| | - Kana Shibata
- Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (T.F.); (F.S.); (Y.T.); (K.S.); (N.K.); (N.K.)
| | - Naruto Katsuragi
- Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (T.F.); (F.S.); (Y.T.); (K.S.); (N.K.); (N.K.)
| | - Nobutaka Koibuchi
- Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (T.F.); (F.S.); (Y.T.); (K.S.); (N.K.); (N.K.)
| | - Kaori Akazawa
- Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (K.A.); (Y.K.); (K.S.)
| | - Yuko Kanemoto
- Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (K.A.); (Y.K.); (K.S.)
| | - Hidehito Kuroyanagi
- Department of Biochemistry, Graduate School of Medicine, University of the Ryukyu, Okinawa 903-0213, Japan;
| | - Kenzo Shimazu
- Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (K.A.); (Y.K.); (K.S.)
| | - Hiromi Rakugi
- Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
| | - Ryuichi Morishita
- Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (T.F.); (F.S.); (Y.T.); (K.S.); (N.K.); (N.K.)
- Correspondence: ; Tel.: +81-6-6210-8352; Fax: +81-6-6210-8354
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Freeman-Cook K, Hoffman RL, Miller N, Almaden J, Chionis J, Zhang Q, Eisele K, Liu C, Zhang C, Huser N, Nguyen L, Costa-Jones C, Niessen S, Carelli J, Lapek J, Weinrich SL, Wei P, McMillan E, Wilson E, Wang TS, McTigue M, Ferre RA, He YA, Ninkovic S, Behenna D, Tran KT, Sutton S, Nagata A, Ornelas MA, Kephart SE, Zehnder LR, Murray B, Xu M, Solowiej JE, Visswanathan R, Boras B, Looper D, Lee N, Bienkowska JR, Zhu Z, Kan Z, Ding Y, Mu XJ, Oderup C, Salek-Ardakani S, White MA, VanArsdale T, Dann SG. Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor. Cancer Cell 2021; 39:1404-1421.e11. [PMID: 34520734 DOI: 10.1016/j.ccell.2021.08.009] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 06/03/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022]
Abstract
The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.
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Affiliation(s)
- Kevin Freeman-Cook
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Robert L Hoffman
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Nichol Miller
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Jonathan Almaden
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - John Chionis
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Qin Zhang
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Koleen Eisele
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Chaoting Liu
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Cathy Zhang
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Nanni Huser
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Lisa Nguyen
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Cinthia Costa-Jones
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Sherry Niessen
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Jordan Carelli
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - John Lapek
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Scott L Weinrich
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Ping Wei
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Elizabeth McMillan
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Elizabeth Wilson
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Tim S Wang
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Michele McTigue
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Rose Ann Ferre
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - You-Ai He
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Sacha Ninkovic
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Douglas Behenna
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Khanh T Tran
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Scott Sutton
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Asako Nagata
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Martha A Ornelas
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Susan E Kephart
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Luke R Zehnder
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Brion Murray
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Meirong Xu
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - James E Solowiej
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Ravi Visswanathan
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Britton Boras
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - David Looper
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Nathan Lee
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Jadwiga R Bienkowska
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Zhou Zhu
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Zhengyan Kan
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Ying Ding
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Xinmeng Jasmine Mu
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Cecilia Oderup
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Shahram Salek-Ardakani
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Michael A White
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Todd VanArsdale
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA.
| | - Stephen G Dann
- Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA.
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Rintala TJ, Federico A, Latonen L, Greco D, Fortino V. A systematic comparison of data- and knowledge-driven approaches to disease subtype discovery. Brief Bioinform 2021; 22:6350885. [PMID: 34396389 PMCID: PMC8575038 DOI: 10.1093/bib/bbab314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/05/2021] [Accepted: 07/20/2021] [Indexed: 12/14/2022] Open
Abstract
Typical clustering analysis for large-scale genomics data combines two unsupervised learning techniques: dimensionality reduction and clustering (DR-CL) methods. It has been demonstrated that transforming gene expression to pathway-level information can improve the robustness and interpretability of disease grouping results. This approach, referred to as biological knowledge-driven clustering (BK-CL) approach, is often neglected, due to a lack of tools enabling systematic comparisons with more established DR-based methods. Moreover, classic clustering metrics based on group separability tend to favor the DR-CL paradigm, which may increase the risk of identifying less actionable disease subtypes that have ambiguous biological and clinical explanations. Hence, there is a need for developing metrics that assess biological and clinical relevance. To facilitate the systematic analysis of BK-CL methods, we propose a computational protocol for quantitative analysis of clustering results derived from both DR-CL and BK-CL methods. Moreover, we propose a new BK-CL method that combines prior knowledge of disease relevant genes, network diffusion algorithms and gene set enrichment analysis to generate robust pathway-level information. Benchmarking studies were conducted to compare the grouping results from different DR-CL and BK-CL approaches with respect to standard clustering evaluation metrics, concordance with known subtypes, association with clinical outcomes and disease modules in co-expression networks of genes. No single approach dominated every metric, showing the importance multi-objective evaluation in clustering analysis. However, we demonstrated that, on gene expression data sets derived from TCGA samples, the BK-CL approach can find groupings that provide significant prognostic value in both breast and prostate cancers.
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Affiliation(s)
- Teemu J Rintala
- Institute of Biomedicine University of Eastern Finland, Yliopistonranta 1 E, 70210 Kuopio, Finland
| | - Antonio Federico
- Faculty of Medicine and Health Technology Tampere University, Kalevantie, 4 33100 Tampere, Finland.,BioMediTech Institute Tampere University, Kalevantie 4, 33100 Tampere, Finland
| | - Leena Latonen
- Institute of Biomedicine University of Eastern Finland, Yliopistonranta 1 E, 70210 Kuopio, Finland
| | - Dario Greco
- Faculty of Medicine and Health Technology Tampere University, Kalevantie, 4 33100 Tampere, Finland.,BioMediTech Institute Tampere University, Kalevantie 4, 33100 Tampere, Finland.,Institute of Biotechnology University of Helsinki, Viikinkaari 5d, 00014 Helsinki, Finland
| | - Vittorio Fortino
- Institute of Biomedicine University of Eastern Finland, Yliopistonranta 1 E, 70210 Kuopio, Finland
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50
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Kumar V, Haldar S, Das NS, Ghosh S, Dhankhar P, Sircar D, Roy P. Pterostilbene-isothiocyanate inhibits breast cancer metastasis by selectively blocking IKK-β/NEMO interaction in cancer cells. Biochem Pharmacol 2021; 192:114717. [PMID: 34352281 DOI: 10.1016/j.bcp.2021.114717] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/11/2021] [Accepted: 07/29/2021] [Indexed: 12/31/2022]
Abstract
Metastasis, the main cause of breast cancer-associated fatalities, relies on many regular pathways involved in normal cell physiology and metabolism, thus, making it challenging to identify disease-specific therapeutic target(s). Chemically synthesized anti-metastatic agents are preferred for their fast and robust actions. However, these agents have adverse side effects, thus, increasingly favouring the identification of phytocompounds as suitable alternatives. Resveratrol and pterostilbene have long been established as potent anti-cancer agents. Earlier studies from our laboratory documented the anti-cancer activities associated with pterostilbene-isothiocyanate (PTER-ITC), a derivative of pterostilbene. The current study focuses on evaluating the anti-metastatic property of PTER-ITC and the underlying mechanism, by employing in silico, in vitro, and in vivo approaches. The significant anti-metastatic activity of PTER-ITC was observed in vitro against breast cancer metastatic cell line (MDA-MB-231) and in vivo in the 4T1 cell-induced metastatic mice model. Epithelial-mesenchymal transition (EMT), a hallmark of metastasis regulated by the transcription factors, Snail1 and Twist, was found to be reverted in vitro by PTER-ITC treatment. PTER-ITC blocked the activation of NF-κB/p65 and its concomitant nuclear translocation, resulting in the transcriptional repression of its target genes, Snail1 and Twist. PTER-ITC prevented the formation of IKK complex, central to NF-κB activation, by binding to the NEMO-binding domain (NBD) of IKK-β and inhibiting its interaction with NEMO (NF-κB essential modulator). According to our observations, PTER-ITC attenuated NF-κB activation selectively in cancerous cells. In conclusion, this study demonstrated that PTER-ITC is a potent anti-metastatic agent capable of targeting physiologically important pathways in a cancer-specific manner.
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Affiliation(s)
- Viney Kumar
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Uttarakhand 247667, India
| | - Swati Haldar
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Uttarakhand 247667, India
| | - Neeladri Singha Das
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Uttarakhand 247667, India
| | - Souvik Ghosh
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Uttarakhand 247667, India; Tissue Engineering Laboratory, Centre for Nanotechnology, Indian Institute of Technology Roorkee, Uttarakhand 247667, India
| | - Poonam Dhankhar
- Structural and Protein Engineering Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Uttarakhand 247667, India
| | - Debabrata Sircar
- Plant Molecular Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Uttarakhand 247667, India
| | - Partha Roy
- Molecular Endocrinology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Uttarakhand 247667, India.
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