|
1
|
Molina Panadero I, Falcón Torres J, Hmadcha A, Princiotto S, Cutarella L, Mori M, Dallavalle S, Christodoulou MS, Smani Y. Antibacterial activity of tamoxifen derivatives against methicillin-resistant Staphylococcus aureus. Front Pharmacol 2025; 16:1549288. [PMID: 40371342 PMCID: PMC12075203 DOI: 10.3389/fphar.2025.1549288] [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: 12/20/2024] [Accepted: 04/11/2025] [Indexed: 05/16/2025] Open
Abstract
The development of new antimicrobial therapeutic strategies requires urgent attention to prevent the tens of millions of deaths predicted to occur by 2050 as a result of multidrug-resistant (MDR) bacterial infections. This study aimed to discover new tamoxifen derivatives with antimicrobial potential, particularly targeting methicillin-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentration (MIC) of 22 tamoxifen derivatives was determined against S. aureus reference and MRSA strains using microdilution assays. The antibacterial effects of selected tamoxifen derivatives against MRSA (USA7 strain) were assessed through bacterial growth assays. Additionally, bacterial membrane permeability and molecular dynamics (MD) simulation assays were performed. The MIC of the tamoxifen derivatives against reference S. aureus and MRSA strains ranged from to 16 to >64 μg/mL. Bacterial growth assays demonstrated that tamoxifen derivatives 2, 5, and 6, the only compounds bearing the electron-donating hydroxyl group in the para position on both phenyl rings of the tamoxifen skeleton, dose-dependently reduced the growth of the USA7 strain. Moreover, treatment of MRSA with derivatives 2 and 5 resulted in a slight increase of membrane permeabilization. Extensive MD simulations on the interaction between 5 and 6 and the S. aureus membrane model suggest that the compounds do not act by destabilizing the membrane integrity. These findings suggest that tamoxifen derivatives exhibit antibacterial activity against MRSA, potentially broadening the spectrum of available drug treatments for combating antimicrobial-resistant S. aureus.
Collapse
Affiliation(s)
- Irene Molina Panadero
- Andalusian Center of Developmental Biology, Consejo Superior de Investigaciones Científicas (CSIC), University of Pablo de Olavide - Seville, Seville, Spain
| | - Javier Falcón Torres
- Andalusian Center of Developmental Biology, Consejo Superior de Investigaciones Científicas (CSIC), University of Pablo de Olavide - Seville, Seville, Spain
| | - Abdelkrim Hmadcha
- Department of Molecular Biology and Biochemical Engineering, University of Pablo de Olavide, Seville, Spain
- Biosanitary Research Institute (IIB-VIU), Valencian International University (VIU), Valencia, Spain
| | - Salvatore Princiotto
- Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Milan, Italy
| | - Luigi Cutarella
- Department f Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Mattia Mori
- Department f Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Sabrina Dallavalle
- Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Milan, Italy
| | - Michael S. Christodoulou
- Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Milan, Italy
| | - Younes Smani
- Andalusian Center of Developmental Biology, Consejo Superior de Investigaciones Científicas (CSIC), University of Pablo de Olavide - Seville, Seville, Spain
- Department of Molecular Biology and Biochemical Engineering, University of Pablo de Olavide, Seville, Spain
| |
Collapse
|
|
2
|
Nakashoji A, Bhattacharya A, Ozawa H, Haratake N, Shigeta K, Fushimi A, Yamashita N, Matsui A, Kure S, Kameyama T, Takeuchi M, Fukuda K, Yokoe T, Nagayama A, Hayahsida T, Kitagawa Y, Liu R, Giordano A, Jeselsohn R, Shapiro GI, Kufe D. MUC1-C dependency in drug resistant HR+/HER2- breast cancer identifies a new target for antibody-drug conjugate treatment. NPJ Breast Cancer 2025; 11:39. [PMID: 40287441 PMCID: PMC12033257 DOI: 10.1038/s41523-025-00751-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 03/27/2025] [Indexed: 04/29/2025] Open
Abstract
Treatment of hormone receptor (HR)-positive, HER2-negative breast cancer (HR+/HER2- BC) is limited by resistance to endocrine therapy (ET) and CDK4/6 inhibitors. There is no known common pathway that confers resistance to these agents. We report that (i) the MUC1 gene is upregulated in HR+/HER2- BCs and (ii) the MUC1-C protein regulates estrogen receptor alpha (ER)-driven transcriptomes. Mechanistically, we demonstrate that MUC1-C is necessary for expression of SRC-3 and MED1 coactivators that drive ER-mediated target gene transcription. Cells with ESR1 mutations that confer ET resistance, as well as cells with acquired resistance to the CDK4/6 inhibitor abemaciclib, are dependent on MUC1-C for (i) expression of these coactivators and ER target genes, (ii) survival, and (iii) self-renewal capacity. In support of these results, we show that treatment of HR+/HER2- BC cells with an anti-MUC1-C antibody-drug conjugate (ADC) effectively inhibits survival, self-renewal and tumorgenicity. These findings indicate that MUC1-C is a common effector of drug-resistant HR+/HER2- BC cells and is a potential target for their treatment.
Collapse
Affiliation(s)
- Ayako Nakashoji
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - Hiroki Ozawa
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Naoki Haratake
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Keisuke Shigeta
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Atsushi Fushimi
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Nami Yamashita
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Akira Matsui
- Department of Breast Surgery, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
| | - Shoko Kure
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Tomoe Kameyama
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Makoto Takeuchi
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Kazumasa Fukuda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Takamichi Yokoe
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Aiko Nagayama
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Tetsu Hayahsida
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Renyan Liu
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Antonio Giordano
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Rinath Jeselsohn
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - Donald Kufe
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
3
|
Jiang C, Zhu Y, Zhang J, Chen H, Li W, Xie R, Kong L, Chen L, Chen X, Huang H, Xu S. NR4A1 suppresses breast cancer growth by repressing c-Fos-mediated lipid and redox dyshomeostasis. Exp Mol Med 2025; 57:804-819. [PMID: 40164686 PMCID: PMC12045962 DOI: 10.1038/s12276-025-01430-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 12/31/2024] [Accepted: 01/13/2025] [Indexed: 04/02/2025] Open
Abstract
The specific function of NR4A1 as a transcriptional regulator in cancer remains unclear. Here we report the biological effect of NR4A1 in suppressing breast cancer (BC) growth. We found that NR4A1 deficiency was correlated with BC progression in the clinic. Genetic deletion of NR4A1 in BC cells significantly promoted cellular proliferation and tumor growth. Moreover, global metabolome screening indicated that the deletion of NR4A1 resulted in tumor lipid remodeling and phospholipid accumulation, which was accompanied by increases in fatty acid and lipid uptake. In addition, NR4A1 knockout induced oxidative stress that aggravated redox balance disruption. Mechanistically, transcriptomic and epigenomic analyses revealed that NR4A1 restrained BC cell proliferation by directly interacting with c-Fos and competitively inhibiting c-Fos binding to the promoter of the target gene PRDX6, which is involved in lipid and redox homeostasis. Notably, we confirmed that the treatment of BC cells with the selective NR4A1 agonist cytosporone B significantly activated the expression of NR4A1, followed by increased interaction between NR4A1 and c-Fos, thereby interfering with c-Fos-mediated transcriptional regulation of BC cell growth. Thus, NR4A1 plays a vital role in reducing the c-Fos-induced activation of downstream signaling cascades in BC, suggesting that agents that activate NR4A1 may be potential therapeutic strategies.
Collapse
Affiliation(s)
- Cen Jiang
- Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
| | - Youzhi Zhu
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Thyroid and Breast Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Junsi Zhang
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Huaying Chen
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Weiwei Li
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Ruiwang Xie
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Lingjun Kong
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Thyroid and Breast Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Ling Chen
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Thyroid and Breast Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Xiangjin Chen
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Thyroid and Breast Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Huifang Huang
- Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
| | - Sunwang Xu
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
- Department of Thyroid and Breast Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
- Fujian Provincial Key Laboratory of Precision Medicine for Cancer, Fuzhou, China.
| |
Collapse
|
|
4
|
Adeluola AA, Radomska HS, Wilson TA, Kulp SK, Kabat A, Helms TH, Mayo AK, Montgomery EJ, Thomas J, Marcho LM, Costa T, Fukuda M, Kang DD, Vibhute S, Wang D, Bennett CE, Coss CC. The elucidation of species-specific receptor pharmacology: A case study using subtype-selective para- and meta-carborane estrogen receptor agonists. J Pharmacol Exp Ther 2025; 392:100001. [PMID: 39892992 DOI: 10.1124/jpet.123.001874] [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: 12/11/2023] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/29/2024] Open
Abstract
Estrogen receptors (ERs) are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of ERβ is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERβ without activating ERα is challenging due to the high sequence and structural homology between the receptor subtypes. We assessed the impact of structural modifications to the parent compound OSU-ERβ-12 on receptor subtype binding selectivity using cell-free binding assays. Functional selectivity was evaluated by transactivation in HEK-293 cells overexpressing human or murine ERs. In vivo selectivity was examined through the uterotrophic effects of the analogs after oral administration in estrogen-naïve female mice. Furthermore, we evaluated the in vivo pharmacokinetics of the analogs following single-dose intravenous and oral administration. Regarding selectivity, a single compound exhibited greater functional selectivity than OSU-ERβ-12 for human ERβ. However, like others in the meta-carborane series, its poor in vivo pharmacokinetics limit its suitability for further development. Surprisingly, and at odds with their pharmacokinetic and in vitro human activity data, most analogs potently induced uterotrophic effects in estrogen-naïve female mice. Further investigation of activity in HEK-293 cells expressing murine ERs revealed species-specific differences in the ER subtype selectivity of these analogs. Our findings highlight species-specific receptor pharmacology and the challenges it poses to characterizing developmental therapeutics in preclinical species. SIGNIFICANCE STATEMENT: This study investigates para- and meta-substituted carborane analogs targeting estrogen receptors (ERs), revealing the greater selectivity of carborane analogs for human ERβ compared to the mouse ortholog. These findings shed light on the intricacies of using preclinical species in drug development to predict human pharmacology. The report also provides insights for the refinement and optimization of carborane analogs as potential therapeutic agents for estrogen-related disease states.
Collapse
Affiliation(s)
- Adeoluwa A Adeluola
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Hanna S Radomska
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Tyler A Wilson
- Medicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Samuel K Kulp
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Alyssa Kabat
- Charles River Laboratories, Worcester, Massachusetts
| | - Timothy H Helms
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Abigail K Mayo
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Emma J Montgomery
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Justin Thomas
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Lynn M Marcho
- Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, Ohio
| | - Travis Costa
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Mayu Fukuda
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Diana D Kang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Sandip Vibhute
- Medicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Dasheng Wang
- Medicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Chad E Bennett
- Medicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Christopher C Coss
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio; Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
| |
Collapse
|
|
5
|
Toska E. Epigenetic mechanisms of cancer progression and therapy resistance in estrogen-receptor (ER+) breast cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189097. [PMID: 38518961 DOI: 10.1016/j.bbcan.2024.189097] [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: 01/08/2024] [Revised: 03/16/2024] [Accepted: 03/19/2024] [Indexed: 03/24/2024]
Abstract
Estrogen receptor-positive (ER+) breast cancer is the most frequent breast cancer subtype. Agents targeting the ER signaling pathway have been successful in reducing mortality from breast cancer for decades. However, mechanisms of resistance to these treatments arise, especially in the metastatic setting. Recently, it has been recognized that epigenetic dysregulation is a common feature that facilitates the acquisition of cancer hallmarks across cancer types, including ER+ breast cancer. Alterations in epigenetic regulators and transcription factors (TF) coupled with changes to the chromatin landscape have been found to orchestrate breast oncogenesis, metastasis, and the development of a resistant phenotype. Here, we review recent advances in our understanding of how the epigenome dictates breast cancer tumorigenesis and resistance to targeted therapies and discuss novel therapeutic interventions for overcoming resistance.
Collapse
Affiliation(s)
- Eneda Toska
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University, Baltimore, MD, USA; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA.
| |
Collapse
|
|
6
|
Rega C, Kozik Z, Yu L, Tsitsa I, Martin LA, Choudhary J. Exploring the Spatial Landscape of the Estrogen Receptor Proximal Proteome With Antibody-Based Proximity Labeling. Mol Cell Proteomics 2024; 23:100702. [PMID: 38122900 PMCID: PMC10831774 DOI: 10.1016/j.mcpro.2023.100702] [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: 11/07/2023] [Accepted: 12/17/2023] [Indexed: 12/23/2023] Open
Abstract
Estrogen receptor α (ERα) drives the transcription of genes involved in breast cancer (BC) progression, relying on coregulatory protein recruitment for its transcriptional and biological activities. Mutation of ERα as well as aberrant recruitment of its regulatory proteins contribute to tumor adaptation and drug resistance. Therefore, understanding the dynamic changes in ERα protein interaction networks is crucial for elucidating drug resistance mechanisms in BC. Despite progress in studying ERα-associated proteins, capturing subcellular transient interactions remains challenging and, as a result, significant number of important interactions remain undiscovered. In this study, we employed biotinylation by antibody recognition (BAR), an innovative antibody-based proximity labeling (PL) approach, coupled with mass spectrometry to investigate the ERα proximal proteome and its changes associated with resistance to aromatase inhibition, a key therapy used in the treatment of ERα-positive BC. We show that BAR successfully detected most of the known ERα interactors and mainly identified nuclear proteins, using either an epitope tag or endogenous antibody to target ERα. We further describe the ERα proximal proteome rewiring associated with resistance applying BAR to a panel of isogenic cell lines modeling tumor adaptation in the clinic. Interestingly, we find that ERα associates with some of the canonical cofactors in resistant cells and several proximal proteome changes are due to increased expression of ERα. Resistant models also show decreased levels of estrogen-regulated genes. Sensitive and resistant cells harboring a mutation in the ERα (Y537C) revealed a similar proximal proteome. We provide an ERα proximal protein network covering several novel ERα-proximal partners. These include proteins involved in highly dynamic processes such as sumoylation and ubiquitination difficult to detect with traditional protein interaction approaches. Overall, we present BAR as an effective approach to investigate the ERα proximal proteome in a spatial context and demonstrate its application in different experimental conditions.
Collapse
Affiliation(s)
- Camilla Rega
- Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
| | - Zuzanna Kozik
- Division of Cancer Biology, The Institute of Cancer Research, London, United Kingdom
| | - Lu Yu
- Division of Cancer Biology, The Institute of Cancer Research, London, United Kingdom
| | - Ifigenia Tsitsa
- Division of Cancer Biology, The Institute of Cancer Research, London, United Kingdom
| | - Lesley-Ann Martin
- Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom
| | - Jyoti Choudhary
- Division of Cancer Biology, The Institute of Cancer Research, London, United Kingdom.
| |
Collapse
|
|
7
|
Stossi F, Rivera Tostado A, Johnson HL, Mistry RM, Mancini MG, Mancini MA. Gene transcription regulation by ER at the single cell and allele level. Steroids 2023; 200:109313. [PMID: 37758052 PMCID: PMC10842394 DOI: 10.1016/j.steroids.2023.109313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/12/2023] [Accepted: 09/23/2023] [Indexed: 10/03/2023]
Abstract
In this short review we discuss the current view of how the estrogen receptor (ER), a pivotal member of the nuclear receptor superfamily of transcription factors, regulates gene transcription at the single cell and allele level, focusing on in vitro cell line models. We discuss central topics and new trends in molecular biology including phenotypic heterogeneity, single cell sequencing, nuclear phase separated condensates, single cell imaging, and image analysis methods, with particular focus on the methodologies and results that have been reported in the last few years using microscopy-based techniques. These observations augment the results from biochemical assays that lead to a much more complex and dynamic view of how ER, and arguably most transcription factors, act to regulate gene transcription.
Collapse
Affiliation(s)
- Fabio Stossi
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States; GCC Center for Advanced Microscopy and Image Informatics, Houston, TX, United States.
| | | | - Hannah L Johnson
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States; GCC Center for Advanced Microscopy and Image Informatics, Houston, TX, United States
| | - Ragini M Mistry
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States; GCC Center for Advanced Microscopy and Image Informatics, Houston, TX, United States
| | - Maureen G Mancini
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States; GCC Center for Advanced Microscopy and Image Informatics, Houston, TX, United States
| | - Michael A Mancini
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States; GCC Center for Advanced Microscopy and Image Informatics, Houston, TX, United States; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, United States.
| |
Collapse
|
|
8
|
Anabel Sinberger L, Zahavi T, Sonnenblick A, Salmon-Divon M. Coexistent ARID1A-PIK3CA mutations are associated with immune-related pathways in luminal breast cancer. Sci Rep 2023; 13:20911. [PMID: 38017109 PMCID: PMC10684499 DOI: 10.1038/s41598-023-48002-x] [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: 07/11/2023] [Accepted: 11/21/2023] [Indexed: 11/30/2023] Open
Abstract
Up to 40% of luminal breast cancer patients carry activating mutations in the PIK3CA gene. PIK3CA mutations commonly co-occur with other mutations, but the implication of this co-occurrence may vary according to the specific genes involved. Here, we characterized a subgroup of luminal breast cancer expressing co-mutations in ARID1A and PIK3CA genes and identified their effect on important signaling pathways. Our study included 2609 primary breast cancer samples from the TCGA and METABRIC datasets that were classified based on tumor subtype and the existence of mutations in PIK3CA and ARID1A genes. Differential expression and WGCNA analyses were performed to detect molecular modules affected by the existence of the mutations. Our results reveal various evidence for the involvement of immune-related pathways in luminal tumors harboring ARID1A and PIK3CA mutations, as well as a unique Tumor-infiltrated immune cells composition. We also identified seven key hub genes in the ARID1A-PIK3CA mutated tumors associated with immune-related pathways: CTLA4, PRF1, LCK, CD3E, CD247, ZAP70, and LCP2. Collectively, these results indicate an immune system function that may contribute to tumor survival. Our data induced a hypothesis that ARID1A and PIK3CA mutations' co-occurrence might predict responses to immunotherapy in luminal BC and, if validated, could guide immunotherapy development.
Collapse
Affiliation(s)
| | - Tamar Zahavi
- Department of Molecular Biology, Ariel University, Ariel, Israel
| | - Amir Sonnenblick
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Mali Salmon-Divon
- Department of Molecular Biology, Ariel University, Ariel, Israel.
- Adelson School of Medicine, Ariel University, Ariel, Israel.
| |
Collapse
|
|
9
|
Xu D, Forbes AN, Cohen S, Palladino A, Karadimitriou T, Khurana E. Recapitulation of patient-specific 3D chromatin conformation using machine learning. CELL REPORTS METHODS 2023; 3:100578. [PMID: 37673071 PMCID: PMC10545938 DOI: 10.1016/j.crmeth.2023.100578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 04/05/2023] [Accepted: 08/10/2023] [Indexed: 09/08/2023]
Abstract
Regulatory networks containing enhancer-gene edges define cellular states. Multiple efforts have revealed these networks for reference tissues and cell lines by integrating multi-omics data. However, the methods developed cannot be applied for large patient cohorts due to the infeasibility of chromatin immunoprecipitation sequencing (ChIP-seq) for limited biopsy material. We trained machine-learning models using chromatin interaction analysis with paired-end tag sequencing (ChIA-PET) and high-throughput chromosome conformation capture combined with chromatin immunoprecipitation (HiChIP) data that can predict connections using only assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA-seq data as input, which can be generated from biopsies. Our method overcomes limitations of correlation-based approaches that cannot distinguish between distinct target genes of given enhancers or between active vs. poised states in different samples, a hallmark of network rewiring in cancer. Application of our model on 371 samples across 22 cancer types revealed 1,780 enhancer-gene connections for 602 cancer genes. Using CRISPR interference (CRISPRi), we validated enhancers predicted to regulate ESR1 in estrogen receptor (ER)+ breast cancer and A1CF in liver hepatocellular carcinoma.
Collapse
Affiliation(s)
- Duo Xu
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Andre Neil Forbes
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Sandra Cohen
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Ann Palladino
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA
| | | | - Ekta Khurana
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
| |
Collapse
|
|
10
|
Kiliti AJ, Sharif GM, Martin MB, Wellstein A, Riegel AT. AIB1/SRC-3/NCOA3 function in estrogen receptor alpha positive breast cancer. Front Endocrinol (Lausanne) 2023; 14:1250218. [PMID: 37711895 PMCID: PMC10498919 DOI: 10.3389/fendo.2023.1250218] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023] Open
Abstract
The estrogen receptor alpha (ERα) is a steroid receptor that is pivotal in the initiation and progression of most breast cancers. ERα regulates gene transcription through recruitment of essential coregulators, including the steroid receptor coactivator AIB1 (Amplified in Breast Cancer 1). AIB1 itself is an oncogene that is overexpressed in a subset of breast cancers and is known to play a role in tumor progression and resistance to endocrine therapy through multiple mechanisms. Here we review the normal and pathological functions of AIB1 in regard to its ERα-dependent and ERα-independent actions, as well as its genomic conservation and protein evolution. We also outline the efforts to target AIB1 in the treatment of breast cancer.
Collapse
Affiliation(s)
- Amber J. Kiliti
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, United States
- Department of Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, DC, United States
| | - Ghada M. Sharif
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, United States
| | - Mary Beth Martin
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, United States
- Department of Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, DC, United States
| | - Anton Wellstein
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, United States
| | - Anna T. Riegel
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, United States
| |
Collapse
|
|
11
|
Bettecken A, Heß L, Hölzen L, Reinheckel T. Dipeptidyl-Aminopeptidases 8 and 9 Regulate Autophagy and Tamoxifen Response in Breast Cancer Cells. Cells 2023; 12:2031. [PMID: 37626841 PMCID: PMC10453625 DOI: 10.3390/cells12162031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/02/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
The cytosolic dipeptidyl-aminopeptidases 8 (DPP8) and 9 (DPP9) belong to the DPPIV serine proteases with the unique characteristic of cleaving off a dipeptide post-proline from the N-termini of substrates. To study the role of DPP8 and DPP9 in breast cancer, MCF-7 cells (luminal A-type breast cancer) and MDA.MB-231 cells (basal-like breast cancer) were used. The inhibition of DPP8/9 by 1G244 increased the number of lysosomes in both cell lines. This phenotype was more pronounced in MCF-7 cells, in which we observed a separation of autophagosomes and lysosomes in the cytosol upon DPP8/9 inhibition. Likewise, the shRNA-mediated knockdown of either DPP8 or DPP9 induced autophagy and increased lysosomes. DPP8/9 inhibition as well as the knockdown of the DPPs reduced the cell survival and proliferation of MCF-7 cells. Additional treatment of MCF-7 cells with tamoxifen, a selective estrogen receptor modulator (SERM) used to treat patients with luminal breast tumors, further decreased survival and proliferation, as well as increased cell death. In summary, both DPP8 and DPP9 activities confine macroautophagy in breast cancer cells. Thus, their inhibition or knockdown reduces cell viability and sensitizes luminal breast cancer cells to tamoxifen treatment.
Collapse
Affiliation(s)
- Aaron Bettecken
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Lisa Heß
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Lena Hölzen
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg, 79104 Freiburg, Germany
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Thomas Reinheckel
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg, 79104 Freiburg, Germany
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Centre of Biological Signalling Studies BIOSS, University of Freiburg, 79104 Freiburg, Germany
| |
Collapse
|
|
12
|
Yi J, Wang L, Hu G, Zhang Y, Du J, Ding J, Ji X, Shen H, Huang H, Ye F, Liu W. CircPVT1 promotes ER-positive breast tumorigenesis and drug resistance by targeting ESR1 and MAVS. EMBO J 2023; 42:e112408. [PMID: 37009655 PMCID: PMC10183818 DOI: 10.15252/embj.2022112408] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 02/06/2023] [Accepted: 03/02/2023] [Indexed: 04/04/2023] Open
Abstract
The molecular mechanisms underlying estrogen receptor (ER)-positive breast carcinogenesis and endocrine therapy resistance remain incompletely understood. Here, we report that circPVT1, a circular RNA generated from the lncRNA PVT1, is highly expressed in ERα-positive breast cancer cell lines and tumor samples and is functionally important in promoting ERα-positive breast tumorigenesis and endocrine therapy resistance. CircPVT1 acts as a competing endogenous RNA (ceRNA) to sponge miR-181a-2-3p, promoting the expression of ESR1 and downstream ERα-target genes and breast cancer cell growth. Furthermore, circPVT1 directly interacts with MAVS protein to disrupt the RIGI-MAVS complex formation, inhibiting type I interferon (IFN) signaling pathway and anti-tumor immunity. Anti-sense oligonucleotide (ASO)-targeting circPVT1 inhibits ERα-positive breast cancer cell and tumor growth, re-sensitizing tamoxifen-resistant ERα-positive breast cancer cells to tamoxifen treatment. Taken together, our data demonstrated that circPVT1 can work through both ceRNA and protein scaffolding mechanisms to promote cancer. Thus, circPVT1 may serve as a diagnostic biomarker and therapeutic target for ERα-positive breast cancer in the clinic.
Collapse
Affiliation(s)
- Jia Yi
- Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation ResearchThe First Affiliated Hospital of Xiamen UniversityXiamenChina
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Lei Wang
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Guo‐sheng Hu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Yue‐ying Zhang
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Jiao Du
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Jian‐cheng Ding
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Xiang Ji
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Hai‐feng Shen
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Hai‐hua Huang
- Department of Pathology, The Second Affiliated HospitalShantou University Medical CollegeShantouChina
| | - Feng Ye
- Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation ResearchThe First Affiliated Hospital of Xiamen UniversityXiamenChina
| | - Wen Liu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| |
Collapse
|
|
13
|
Aylon Y, Furth N, Mallel G, Friedlander G, Nataraj NB, Dong M, Hassin O, Zoabi R, Cohen B, Drendel V, Salame TM, Mukherjee S, Harpaz N, Johnson R, Aulitzky WE, Yarden Y, Shema E, Oren M. Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis. Nat Commun 2022; 13:7199. [PMID: 36443319 PMCID: PMC9705295 DOI: 10.1038/s41467-022-34863-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 11/10/2022] [Indexed: 11/29/2022] Open
Abstract
Breast cancer, the most frequent cancer in women, is generally classified into several distinct histological and molecular subtypes. However, single-cell technologies have revealed remarkable cellular and functional heterogeneity across subtypes and even within individual breast tumors. Much of this heterogeneity is attributable to dynamic alterations in the epigenetic landscape of the cancer cells, which promote phenotypic plasticity. Such plasticity, including transition from luminal to basal-like cell identity, can promote disease aggressiveness. We now report that the tumor suppressor LATS1, whose expression is often downregulated in human breast cancer, helps maintain luminal breast cancer cell identity by reducing the chromatin accessibility of genes that are characteristic of a "basal-like" state, preventing their spurious activation. This is achieved via interaction of LATS1 with the NCOR1 nuclear corepressor and recruitment of HDAC1, driving histone H3K27 deacetylation near NCOR1-repressed "basal-like" genes. Consequently, decreased expression of LATS1 elevates the expression of such genes and facilitates slippage towards a more basal-like phenotypic identity. We propose that by enforcing rigorous silencing of repressed genes, the LATS1-NCOR1 axis maintains luminal cell identity and restricts breast cancer progression.
Collapse
Affiliation(s)
- Yael Aylon
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Noa Furth
- grid.13992.300000 0004 0604 7563Department of Immunology and Regenerative Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Giuseppe Mallel
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Gilgi Friedlander
- grid.13992.300000 0004 0604 7563Department of Life Sciences Core Facilities, The Nancy & Stephen Grand Israel National Center for Personalized Medicine (G-INCPM), The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Nishanth Belugali Nataraj
- grid.13992.300000 0004 0604 7563Department of Immunology and Regenerative Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Meng Dong
- grid.502798.10000 0004 0561 903XDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany
| | - Ori Hassin
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Rawan Zoabi
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Benjamin Cohen
- grid.13992.300000 0004 0604 7563Department of Immunology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Vanessa Drendel
- grid.416008.b0000 0004 0603 4965Department of Pathology, Robert Bosch Hospital, Stuttgart, Germany
| | - Tomer Meir Salame
- grid.13992.300000 0004 0604 7563Flow Cytometry Unit, Department of Life Sciences Core Facilities, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Saptaparna Mukherjee
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Nofar Harpaz
- grid.13992.300000 0004 0604 7563Department of Immunology and Regenerative Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Randy Johnson
- grid.240145.60000 0001 2291 4776Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Walter E. Aulitzky
- grid.416008.b0000 0004 0603 4965Department of Hematology, Oncology and Palliative Medicine, Robert Bosch Hospital, Stuttgart, Germany
| | - Yosef Yarden
- grid.13992.300000 0004 0604 7563Department of Immunology and Regenerative Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Efrat Shema
- grid.13992.300000 0004 0604 7563Department of Immunology and Regenerative Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Moshe Oren
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| |
Collapse
|
|
14
|
Blawski R, Toska E. A Unique FOXA1-Associated Chromatin State Dictates Therapeutic Resistance in Lobular Breast Cancer. Cancer Res 2022; 82:3668-3670. [PMID: 36245246 PMCID: PMC10084780 DOI: 10.1158/0008-5472.can-22-2594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 11/16/2022]
Abstract
Invasive lobular carcinomas (ILC) are the second most common histologic subtype of breast cancer, accounting for up to 15% of cases. ILC is estrogen receptor (ER) positive, yet its biology is distinct from invasive ductal carcinomas (IDC), and retrospective analyses have indicated a poorer outcome with endocrine therapy. In this issue of Cancer Research, Nardone and colleagues investigated the mechanisms of this differential therapy response in ILC, which cannot be solely explained by the genetic profile of these tumors. The authors conducted a thorough examination of the epigenome of ILC compared with IDC in clinical and preclinical models and revealed an alternative chromatin accessibility state in ILC driven by the pioneer factor FOXA1. FOXA1 regulates its own expression in a feed-forward mechanism by binding to an ILC-unique FOXA1 enhancer site. This results in a FOXA1-ER axis that promotes the transcription of genes associated with tumor progression and tamoxifen resistance. Targeting the FOXA1 enhancer region blocks this transcriptional program and inhibits ILC proliferation. These results shed light on a new epigenetic mechanism driving ILC tumor progression and treatment resistance, which may have profound therapeutic implications. See related article by Nardone et al., p. 3673.
Collapse
Affiliation(s)
- Ryan Blawski
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Eneda Toska
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, Maryland
| |
Collapse
|
|
15
|
Messier TL, Boyd JR, Gordon JAR, Tye CE, Page NA, Toor RH, Zaidi SK, Komm BS, Frietze S, Stein JL, Lian JB, Stein GS. Epigenetic and transcriptome responsiveness to ER modulation by tissue selective estrogen complexes in breast epithelial and breast cancer cells. PLoS One 2022; 17:e0271725. [PMID: 35862394 PMCID: PMC9302754 DOI: 10.1371/journal.pone.0271725] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 07/06/2022] [Indexed: 01/07/2023] Open
Abstract
Selective estrogen receptor modulators (SERMs), including the SERM/SERD bazedoxifene (BZA), are used to treat postmenopausal osteoporosis and may reduce breast cancer (BCa) risk. One of the most persistent unresolved questions regarding menopausal hormone therapy is compromised control of proliferation and phenotype because of short- or long-term administration of mixed-function estrogen receptor (ER) ligands. To gain insight into epigenetic effectors of the transcriptomes of hormone and BZA-treated BCa cells, we evaluated a panel of histone modifications. The impact of short-term hormone treatment and BZA on gene expression and genome-wide epigenetic profiles was examined in ERαneg mammary epithelial cells (MCF10A) and ERα+ luminal breast cancer cells (MCF7). We tested individual components and combinations of 17β-estradiol (E2), estrogen compounds (EC10) and BZA. RNA-seq for gene expression and ChIP-seq for active (H3K4me3, H3K4ac, H3K27ac) and repressive (H3K27me3) histone modifications were performed. Our results show that the combination of BZA with E2 or EC10 reduces estrogen-mediated patterns of histone modifications and gene expression in MCF-7ERα+ cells. In contrast, BZA has minimal effects on these parameters in MCF10A mammary epithelial cells. BZA-induced changes in histone modifications in MCF7 cells are characterized by altered H3K4ac patterns, with changes at distal enhancers of ERα-target genes and at promoters of non-ERα bound proliferation-related genes. Notably, the ERα target gene GREB1 is the most sensitive to BZA treatment. Our findings provide direct mechanistic-based evidence that BZA induces epigenetic changes in E2 and EC10 mediated control of ERα regulatory programs to target distinctive proliferation gene pathways that restrain the potential for breast cancer development.
Collapse
Affiliation(s)
- Terri L. Messier
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
- University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
| | - Joseph R. Boyd
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
| | - Jonathan A. R. Gordon
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
- University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
| | - Coralee E. Tye
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
- University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
| | - Natalie A. Page
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
| | - Rabail H. Toor
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
| | - Sayyed K. Zaidi
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
- University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
| | - Barry S. Komm
- Komm Pharma Consulting LLC, San Francisco, CA, United States of America
| | - Seth Frietze
- University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, United States of America
| | - Janet L. Stein
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
- University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
| | - Jane B. Lian
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
- University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
| | - Gary S. Stein
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
- University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, United States of America
- Department of Surgery, University of Vermont, Burlington, VT, United States of America
| |
Collapse
|
|
16
|
Sukocheva OA, Lukina E, Friedemann M, Menschikowski M, Hagelgans A, Aliev G. The crucial role of epigenetic regulation in breast cancer anti-estrogen resistance: Current findings and future perspectives. Semin Cancer Biol 2022; 82:35-59. [PMID: 33301860 DOI: 10.1016/j.semcancer.2020.12.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/22/2020] [Accepted: 12/03/2020] [Indexed: 02/07/2023]
Abstract
Breast cancer (BC) cell de-sensitization to Tamoxifen (TAM) or other selective estrogen receptor (ER) modulators (SERM) is a complex process associated with BC heterogeneity and the transformation of ER signalling. The most influential resistance-related mechanisms include modifications in ER expression and gene regulation patterns. During TAM/SERM treatment, epigenetic mechanisms can effectively silence ER expression and facilitate the development of endocrine resistance. ER status is efficiently regulated by specific epigenetic tools including hypermethylation of CpG islands within ER promoters, increased histone deacetylase activity in the ER promoter, and/or translational repression by miRNAs. Over-methylation of the ER α gene (ESR1) promoter by DNA methyltransferases was associated with poor prognosis and indicated the development of resistance. Moreover, BC progression and spreading were marked by transformed chromatin remodelling, post-translational histone modifications, and expression of specific miRNAs and/or long non-coding RNAs. Therefore, targeted inhibition of histone acetyltransferases (e.g. MYST3), deacetylases (e.g. HDAC1), and/or demethylases (e.g. lysine-specific demethylase LSD1) was shown to recover and increase BC sensitivity to anti-estrogens. Indicated as a powerful molecular instrument, the administration of epigenetic drugs can regain ER expression along with the activation of tumour suppressor genes, which can in turn prevent selection of resistant cells and cancer stem cell survival. This review examines recent advances in the epigenetic regulation of endocrine drug resistance and evaluates novel anti-resistance strategies. Underlying molecular mechanisms of epigenetic regulation will be discussed, emphasising the utilization of epigenetic enzymes and their inhibitors to re-program irresponsive BCs.
Collapse
Affiliation(s)
- Olga A Sukocheva
- Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia.
| | - Elena Lukina
- Discipline of Biology, College of Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia
| | - Markus Friedemann
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Mario Menschikowski
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Albert Hagelgans
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Gjumrakch Aliev
- Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia; Federal State Budgetary Institution «Research Institute of Human Morphology», 3, Tsyurupy Str., Moscow, 117418, Russian Federation; GALLY International Research Institute, San Antonio, TX, 78229, USA.
| |
Collapse
|
|
17
|
Arruabarrena-Aristorena A, Toska E. Epigenetic Mechanisms Influencing Therapeutic Response in Breast Cancer. Front Oncol 2022; 12:924808. [PMID: 35774123 PMCID: PMC9239340 DOI: 10.3389/fonc.2022.924808] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/05/2022] [Indexed: 12/13/2022] Open
Abstract
The majority of breast cancers are estrogen receptor (ER)+ and agents targeting the ER signaling pathway have markedly increased survival for women with breast cancer for decades. However, therapeutic resistance eventually emerges, especially in the metastatic setting. In the past decade disrupted epigenetic regulatory processes have emerged as major contributors to carcinogenesis in many cancer types. Aberrations in chromatin modifiers and transcription factors have also been recognized as mediators of breast cancer development and therapeutic outcome, and new epigenetic-based therapies in combination with targeted therapies have been proposed. Here we will discuss recent progress in our understanding of the chromatin-based mechanisms of breast tumorigenesis, how these mechanisms affect therapeutic response to standard of care treatment, and discuss new strategies towards therapeutic intervention to overcome resistance.
Collapse
Affiliation(s)
- Amaia Arruabarrena-Aristorena
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- Traslational Prostate Cancer Research Lab, CIC bioGUNE-Basurto, Biocruces Bizkaia Health Research Institute, Derio, Spain
| | - Eneda Toska
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, United States
| |
Collapse
|
|
18
|
Targeting Nuclear Receptors in Lung Cancer—Novel Therapeutic Prospects. Pharmaceuticals (Basel) 2022; 15:ph15050624. [PMID: 35631448 PMCID: PMC9145966 DOI: 10.3390/ph15050624] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 01/27/2023] Open
Abstract
Lung cancer, the second most commonly diagnosed cancer, is the major cause of fatalities worldwide for both men and women, with an estimated 2.2 million new incidences and 1.8 million deaths, according to GLOBOCAN 2020. Although various risk factors for lung cancer pathogenesis have been reported, controlling smoking alone has a significant value as a preventive measure. In spite of decades of extensive research, mechanistic cues and targets need to be profoundly explored to develop potential diagnostics, treatments, and reliable therapies for this disease. Nuclear receptors (NRs) function as transcription factors that control diverse biological processes such as cell growth, differentiation, development, and metabolism. The aberrant expression of NRs has been involved in a variety of disorders, including cancer. Deregulation of distinct NRs in lung cancer has been associated with numerous events, including mutations, epigenetic modifications, and different signaling cascades. Substantial efforts have been made to develop several small molecules as agonists or antagonists directed to target specific NRs for inhibiting tumor cell growth, migration, and invasion and inducing apoptosis in lung cancer, which makes NRs promising candidates for reliable lung cancer therapeutics. The current work focuses on the importance of various NRs in the development and progression of lung cancer and highlights the different small molecules (e.g., agonist or antagonist) that influence NR expression, with the goal of establishing them as viable therapeutics to combat lung cancer.
Collapse
|
|
19
|
Role of Estrogens in Menstrual Migraine. Cells 2022; 11:cells11081355. [PMID: 35456034 PMCID: PMC9025552 DOI: 10.3390/cells11081355] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 04/10/2022] [Accepted: 04/11/2022] [Indexed: 11/17/2022] Open
Abstract
Migraine is a major neurological disorder affecting one in nine adults worldwide with a significant impact on health care and socioeconomic systems. Migraine is more prevalent in women than in men, with 17% of all women meeting the diagnostic criteria for migraine. In women, the frequency of migraine attacks shows variations over the menstrual cycle and pregnancy, and the use of combined hormonal contraception (CHC) or hormone replacement therapy (HRT) can unveil or modify migraine disease. In the general population, 18–25% of female migraineurs display a menstrual association of their headache. Here we present an overview on the evidence supporting the role of reproductive hormones, in particular estrogens, in the pathophysiology of migraine. We also analyze the efficacy and safety of prescribing exogenous estrogens as a potential treatment for menstrual-related migraine. Finally, we point to controversial issues and future research areas in the field of reproductive hormones and migraine.
Collapse
|
|
20
|
Epigenetic Factors as Etiological Agents, Diagnostic Markers, and Therapeutic Targets for Luminal Breast Cancer. Biomedicines 2022; 10:biomedicines10040748. [PMID: 35453496 PMCID: PMC9031900 DOI: 10.3390/biomedicines10040748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/16/2022] [Accepted: 03/21/2022] [Indexed: 11/16/2022] Open
Abstract
Luminal breast cancer, an etiologically heterogeneous disease, is characterized by high steroid hormone receptor activity and aberrant gene expression profiles. Endocrine therapy and chemotherapy are promising therapeutic approaches to mitigate breast cancer proliferation and recurrence. However, the treatment of therapy-resistant breast cancer is a major challenge. Recent studies on breast cancer etiology have revealed the critical roles of epigenetic factors in luminal breast cancer tumorigenesis and drug resistance. Tumorigenic epigenetic factor-induced aberrant chromatin dynamics dysregulate the onset of gene expression and consequently promote tumorigenesis and metastasis. Epigenetic dysregulation, a type of somatic mutation, is a high-risk factor for breast cancer progression and therapy resistance. Therefore, epigenetic modulators alone or in combination with other therapies are potential therapeutic agents for breast cancer. Several clinical trials have analyzed the therapeutic efficacy of potential epi-drugs for breast cancer and reported beneficial clinical outcomes, including inhibition of tumor cell adhesion and invasiveness and mitigation of endocrine therapy resistance. This review focuses on recent findings on the mechanisms of epigenetic factors in the progression of luminal breast cancer. Additionally, recent findings on the potential of epigenetic factors as diagnostic biomarkers and therapeutic targets for breast cancer are discussed.
Collapse
|
|
21
|
Özturan D, Morova T, Lack NA. Androgen Receptor-Mediated Transcription in Prostate Cancer. Cells 2022; 11:898. [PMID: 35269520 PMCID: PMC8909478 DOI: 10.3390/cells11050898] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/25/2022] [Accepted: 03/01/2022] [Indexed: 11/16/2022] Open
Abstract
Androgen receptor (AR)-mediated transcription is critical in almost all stages of prostate cancer (PCa) growth and differentiation. This process involves a complex interplay of coregulatory proteins, chromatin remodeling complexes, and other transcription factors that work with AR at cis-regulatory enhancer regions to induce the spatiotemporal transcription of target genes. This enhancer-driven mechanism is remarkably dynamic and undergoes significant alterations during PCa progression. In this review, we discuss the AR mechanism of action in PCa with a focus on how cis-regulatory elements modulate gene expression. We explore emerging evidence of genetic variants that can impact AR regulatory regions and alter gene transcription in PCa. Finally, we highlight several outstanding questions and discuss potential mechanisms of this critical transcription factor.
Collapse
Affiliation(s)
- Doğancan Özturan
- School of Medicine, Koç University, Istanbul 34450, Turkey;
- Koç University Research Centre for Translational Medicine (KUTTAM), Koç University, Istanbul 34450, Turkey
| | - Tunç Morova
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada;
| | - Nathan A. Lack
- School of Medicine, Koç University, Istanbul 34450, Turkey;
- Koç University Research Centre for Translational Medicine (KUTTAM), Koç University, Istanbul 34450, Turkey
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada;
| |
Collapse
|
|
22
|
Gangwar SK, Kumar A, Jose S, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. Nuclear receptors in oral cancer-emerging players in tumorigenesis. Cancer Lett 2022; 536:215666. [DOI: 10.1016/j.canlet.2022.215666] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 12/24/2022]
|
|
23
|
Knoedler JR, Inoue S, Bayless DW, Yang T, Tantry A, Davis CH, Leung NY, Parthasarathy S, Wang G, Alvarado M, Rizvi AH, Fenno LE, Ramakrishnan C, Deisseroth K, Shah NM. A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior. Cell 2022; 185:654-671.e22. [PMID: 35065713 PMCID: PMC8956134 DOI: 10.1016/j.cell.2021.12.031] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/22/2021] [Accepted: 12/20/2021] [Indexed: 01/05/2023]
Abstract
Sex hormones exert a profound influence on gendered behaviors. How individual sex hormone-responsive neuronal populations regulate diverse sex-typical behaviors is unclear. We performed orthogonal, genetically targeted sequencing of four estrogen receptor 1-expressing (Esr1+) populations and identified 1,415 genes expressed differentially between sexes or estrous states. Unique subsets of these genes were distributed across all 137 transcriptomically defined Esr1+ cell types, including estrous stage-specific ones, that comprise the four populations. We used differentially expressed genes labeling single Esr1+ cell types as entry points to functionally characterize two such cell types, BNSTprTac1/Esr1 and VMHvlCckar/Esr1. We observed that these two cell types, but not the other Esr1+ cell types in these populations, are essential for sex recognition in males and mating in females, respectively. Furthermore, VMHvlCckar/Esr1 cell type projections are distinct from those of other VMHvlEsr1 cell types. Together, projection and functional specialization of dimorphic cell types enables sex hormone-responsive populations to regulate diverse social behaviors.
Collapse
Affiliation(s)
- Joseph R Knoedler
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Sayaka Inoue
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Daniel W Bayless
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Taehong Yang
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Adarsh Tantry
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Chung-Ha Davis
- Neurosciences Graduate Program, Stanford University, Stanford, CA 94305, USA
| | - Nicole Y Leung
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | | | - Grace Wang
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Maricruz Alvarado
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Abbas H Rizvi
- Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
| | - Lief E Fenno
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | | | - Karl Deisseroth
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
| | - Nirao M Shah
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Department of Neurobiology, Stanford University, Stanford, CA 94305, USA.
| |
Collapse
|
|
24
|
Patel JM, Jeselsohn RM. Estrogen Receptor Alpha and ESR1 Mutations in Breast Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1390:171-194. [DOI: 10.1007/978-3-031-11836-4_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
25
|
Kowalczyk W, Waliszczak G, Jach R, Dulińska-Litewka J. Steroid Receptors in Breast Cancer: Understanding of Molecular Function as a Basis for Effective Therapy Development. Cancers (Basel) 2021; 13:4779. [PMID: 34638264 PMCID: PMC8507808 DOI: 10.3390/cancers13194779] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 09/18/2021] [Accepted: 09/20/2021] [Indexed: 12/21/2022] Open
Abstract
Breast cancer remains one of the most important health problems worldwide. The family of steroid receptors (SRs), which comprise estrogen (ER), progesterone (PR), androgen (AR), glucocorticoid (GR) and mineralocorticoid (MR) receptors, along with a receptor for a secosteroid-vitamin D, play a crucial role in the pathogenesis of the disease. They function predominantly as nuclear receptors to regulate gene expression, however, their full spectrum of action reaches far beyond this basic mechanism. SRs are involved in a vast variety of interactions with other proteins, including extensive crosstalk with each other. How they affect the biology of a breast cell depends on such factors as post-translational modifications, expression of coregulators, or which SR isoform is predominantly synthesized in a given cellular context. Although ER has been successfully utilized as a breast cancer therapy target for years, research on therapeutic application of other SRs is still ongoing. Designing effective hormone therapies requires thorough understanding of the molecular function of the SRs. Over the past decades, huge amount of data was obtained in multiple studies exploring this field, therefore in this review we attempt to summarize the current knowledge in a comprehensive way.
Collapse
Affiliation(s)
- Wojciech Kowalczyk
- Chair of Medical Biochemistry, Jagiellonian University Medical College, 7 Kopernika St., 31-034 Kraków, Poland; (W.K.); (G.W.)
| | - Grzegorz Waliszczak
- Chair of Medical Biochemistry, Jagiellonian University Medical College, 7 Kopernika St., 31-034 Kraków, Poland; (W.K.); (G.W.)
| | - Robert Jach
- Department of Gynecology and Obstetrics, Jagiellonian University Medical College, 23 Kopernika St., 31-501 Kraków, Poland;
| | - Joanna Dulińska-Litewka
- Chair of Medical Biochemistry, Jagiellonian University Medical College, 7 Kopernika St., 31-034 Kraków, Poland; (W.K.); (G.W.)
| |
Collapse
|
|
26
|
Pavanelli AC, Mangone FR, Barros LRC, Machado-Rugolo J, Capelozzi VL, Nagai MA. Abnormal Long Non-Coding RNAs Expression Patterns Have the Potential Ability for Predicting Survival and Treatment Response in Breast Cancer. Genes (Basel) 2021; 12:genes12070996. [PMID: 34209776 PMCID: PMC8305383 DOI: 10.3390/genes12070996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/11/2021] [Accepted: 06/23/2021] [Indexed: 12/09/2022] Open
Abstract
Abnormal long non-coding RNAs (lncRNAs) expression has been documented to have oncogene or tumor suppressor functions in the development and progression of cancer, emerging as promising independent biomarkers for molecular cancer stratification and patients’ prognosis. Examining the relationship between lncRNAs and the survival rates in malignancies creates new scenarios for precision medicine and targeted therapy. Breast cancer (BRCA) is a heterogeneous malignancy. Despite advances in its molecular classification, there are still gaps to explain in its multifaceted presentations and a substantial lack of biomarkers that can better predict patients’ prognosis in response to different therapeutic strategies. Here, we performed a re-analysis of gene expression data generated using cDNA microarrays in a previous study of our group, aiming to identify differentially expressed lncRNAs (DELncRNAs) with a potential predictive value for response to treatment with taxanes in breast cancer patients. Results revealed 157 DELncRNAs (90 up- and 67 down-regulated). We validated these new biomarkers as having prognostic and predictive value for breast cancer using in silico analysis in public databases. Data from TCGA showed that compared to normal tissue, MIAT was up-regulated, while KCNQ1OT1, LOC100270804, and FLJ10038 were down-regulated in breast tumor tissues. KCNQ1OT1, LOC100270804, and FLJ10038 median levels were found to be significantly higher in the luminal subtype. The ROC plotter platform results showed that reduced expression of these three DElncRNAs was associated with breast cancer patients who did not respond to taxane treatment. Kaplan–Meier survival analysis revealed that a lower expression of the selected lncRNAs was significantly associated with worse relapse-free survival (RFS) in breast cancer patients. Further validation of the expression of these DELncRNAs might be helpful to better tailor breast cancer prognosis and treatment.
Collapse
Affiliation(s)
- Ana Carolina Pavanelli
- Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, Brazil; (A.C.P.); (F.R.M.); (L.R.C.B.)
- Center for Translational Research in Oncology, Cancer Institute of São Paulo, São Paulo 01246-903, Brazil
| | - Flavia Rotea Mangone
- Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, Brazil; (A.C.P.); (F.R.M.); (L.R.C.B.)
- Center for Translational Research in Oncology, Cancer Institute of São Paulo, São Paulo 01246-903, Brazil
| | - Luciana R. C. Barros
- Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, Brazil; (A.C.P.); (F.R.M.); (L.R.C.B.)
- Center for Translational Research in Oncology, Cancer Institute of São Paulo, São Paulo 01246-903, Brazil
| | - Juliana Machado-Rugolo
- Department of Pathology, University of São Paulo Medical School (USP), São Paulo 01246-903, Brazil; (J.M.-R.); (V.L.C.)
- Health Technology Assessment Center (NATS), Clinical Hospital (HCFMB), Medical School of São Paulo State University (UNESP), Botucatu, São Paulo 01246-903, Brazil
| | - Vera L. Capelozzi
- Department of Pathology, University of São Paulo Medical School (USP), São Paulo 01246-903, Brazil; (J.M.-R.); (V.L.C.)
| | - Maria A. Nagai
- Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, Brazil; (A.C.P.); (F.R.M.); (L.R.C.B.)
- Center for Translational Research in Oncology, Cancer Institute of São Paulo, São Paulo 01246-903, Brazil
- Correspondence:
| |
Collapse
|
|
27
|
Arruabarrena-Aristorena A, Toska E. FOXA1 mutations influence the therapeutic response of breast cancer by altering chromatin state. Mol Cell Oncol 2021; 8:1891831. [PMID: 34027035 DOI: 10.1080/23723556.2021.1891831] [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: 10/21/2022]
Abstract
Forkhead box protein A1 (FOXA1) is a pioneer transcription factor that contributes to chromatin opening to allow binding of estrogen receptor (ER) in ER+ breast cancer. Mutations in FOXA1 are recurrent in breast cancer but the functional consequences of these mutations remain unknown. We identified that FOXA1 mutations are associated with worse outcomes to endocrine therapy by inducing alternative chromatin profiles and gene activity in breast cancer.
Collapse
Affiliation(s)
| | - Eneda Toska
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA
| |
Collapse
|
|
28
|
Genome-Wide Analysis Unveils DNA Helicase RECQ1 as a Regulator of Estrogen Response Pathway in Breast Cancer Cells. Mol Cell Biol 2021; 41:MCB.00515-20. [PMID: 33468559 DOI: 10.1128/mcb.00515-20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 01/07/2021] [Indexed: 02/07/2023] Open
Abstract
Susceptibility to breast cancer is significantly increased in individuals with germ line mutations in RECQ1 (also known as RECQL or RECQL1), a gene encoding a DNA helicase essential for genome maintenance. We previously reported that RECQ1 expression predicts clinical outcomes for sporadic breast cancer patients stratified by estrogen receptor (ER) status. Here, we utilized an unbiased integrative genomics approach to delineate a cross talk between RECQ1 and ERα, a known master regulatory transcription factor in breast cancer. We found that expression of ESR1, the gene encoding ERα, is directly activated by RECQ1. More than 35% of RECQ1 binding sites were cobound by ERα genome-wide. Mechanistically, RECQ1 cooperates with FOXA1, the pioneer transcription factor for ERα, to enhance chromatin accessibility at the ESR1 regulatory regions in a helicase activity-dependent manner. In clinical ERα-positive breast cancers treated with endocrine therapy, high RECQ1 and high FOXA1 coexpressing tumors were associated with better survival. Collectively, these results identify RECQ1 as a novel cofactor for ERα and uncover a previously unknown mechanism by which RECQ1 regulates disease-driving gene expression in ER-positive breast cancer cells.
Collapse
|
|
29
|
Epigenetic mechanisms in breast cancer therapy and resistance. Nat Commun 2021; 12:1786. [PMID: 33741974 PMCID: PMC7979820 DOI: 10.1038/s41467-021-22024-3] [Citation(s) in RCA: 241] [Impact Index Per Article: 60.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
Abstract
The majority of breast cancers express the estrogen receptor (ERα) and agents targeting this pathway represent the main treatment modality. Endocrine therapy has proven successful in the treatment of hormone-responsive breast cancer since its early adoption in the 1940s as an ablative therapy. Unfortunately, therapeutic resistance arises, leading to disease recurrence and relapse. Recent studies increased our understanding in how changes to the chromatin landscape and deregulation of epigenetic factors orchestrate the resistant phenotype. Here, we will discuss how the epigenome is an integral determinant in hormone therapy response and why epigenetic factors are promising targets for overcoming clinical resistance. Endocrine therapy has been the mainstay for hormone responsive breast cancer treatment. Here, Garcia-Martinez and colleagues discuss epigenetic mechanisms regulating ER + breast cancer and endocrine therapy resistance, and highlight approaches to rewire the cancer epigenome to improve targeted therapies for this cancer.
Collapse
|
|
30
|
Massah S, Foo J, Li N, Truong S, Nouri M, Xie L, Prins GS, Buttyan R. Gli activation by the estrogen receptor in breast cancer cells: Regulation of cancer cell growth by Gli3. Mol Cell Endocrinol 2021; 522:111136. [PMID: 33347954 DOI: 10.1016/j.mce.2020.111136] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Gli is an oncogenic transcription factor family thought to be involved in breast cancer (BrCa) cell growth. Gli activity is regulated by a post-translational proteolytic process that is suppressed by Hedgehog signaling. In prostate cancer cells, however, Gli activation is mediated by an interaction of active androgen receptor proteins with Gli3 that stabilizes Gli3 in its un-proteolyzed form. Here we show that the estrogen receptor (ER), ERα, also binds Gli3 and activates Gli in BrCa cells. Moreover, we show that ER + BrCa cells are dependent on Gli3 for cancer cell growth. METHODS Transfection with Gli-luciferase reporter was used to report Gli activity in 293FT or BrCa cells (MCF7, T47D, MDA-MB-453) with or without steroid ligands. Co-immunoprecipitation and proximity ligation were used to show association of Gli3 with ERα. Gli3 stability was determined by western blots of BrCa cell extracts. ERα knockdown or destabilization (by fulvestrant) was used to assess how loss of ERα affects estradiol-induced Gli reporter activity, formation of intranuclear ERα-Gli3 complexes and Gli3 stability. Expression of Gli1 and/or other endogenous Gli-target genes in BrCa cells were measured by qPCR in the presence or absence of estradiol. Gli3 knockdown was assessed for effects on BrCa cell growth using the Cyquant assay. RESULTS ERα co-transfection increased Gli reporter activity in 293FT cells that was further increased by estradiol. Gli3 co-precipitated in ERα immunoprecipitates. Acute (2 h) estradiol increased Gli reporter activity and the formation of intranuclear ERα-Gli3 complexes in ER + BrCa cells but more chronic estradiol (48 h) reduced ERα-Gli complexes commensurate with reduced ERα levels. Gli3 stability and endogenous activity was only increased by more chronic estradiol treatment. Fulvestrant or ERα knockdown suppressed E2-induction of Gli activity, intranuclear ERα-Gli3 complexes and stabilization of Gli3. Gli3 knockdown significantly reduced the growth of BrCa cells. CONCLUSIONS ERα interacts with Gli3 in BrCa cells and estradiol treatment leads to Gli3 stabilization and increased expression of Gli-target genes. Furthermore, we found tthat Gli3 is necessary for BrCa cell growth. These results support the idea that the ERα-Gli interaction and Gli3 may be novel targets for effective control of BrCa growth.
Collapse
Affiliation(s)
- Shabnam Massah
- The Vancouver Prostate Centre, Canada; The Department of Urologic Sciences, University of British Columbia, Canada
| | - Jane Foo
- The Vancouver Prostate Centre, Canada; Interdisciplinary Oncology, University of British Columbia, Canada
| | - Na Li
- The Vancouver Prostate Centre, Canada
| | | | | | - Lishi Xie
- The Department of Urology, University of Illinois at Chicago, Canada
| | - Gail S Prins
- The Department of Urology, University of Illinois at Chicago, Canada
| | - Ralph Buttyan
- The Vancouver Prostate Centre, Canada; The Department of Urologic Sciences, University of British Columbia, Canada.
| |
Collapse
|
|
31
|
Cervantes-Badillo MG, Paredes-Villa A, Gómez-Romero V, Cervantes-Roldán R, Arias-Romero LE, Villamar-Cruz O, González-Montiel M, Barrios-García T, Cabrera-Quintero AJ, Rodríguez-Gómez G, Cancino-Villeda L, Zentella-Dehesa A, León-Del-Río A. IFI27/ISG12 Downregulates Estrogen Receptor α Transactivation by Facilitating Its Interaction With CRM1/XPO1 in Breast Cancer Cells. Front Endocrinol (Lausanne) 2020; 11:568375. [PMID: 33117284 PMCID: PMC7575815 DOI: 10.3389/fendo.2020.568375] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/16/2020] [Indexed: 11/13/2022] Open
Abstract
The estrogen receptor alpha (ERα) is a ligand-activated transcription factor whose activity is modulated by its interaction with multiple protein complexes. In this work, we have identified the protein interferon alpha inducible protein 27 (IFI27/ISG12) as a novel ERα-associated protein. IFI27/ISG12 transcription is regulated by interferon and estradiol and its overexpression is associated to reduced overall survival in ER+ breast cancer patients but its function in mammary gland tissue remains elusive. In this study we showed that overexpression of IFI27/ISG12 in breast cancer cells attenuates ERα transactivation activity and the expression of ERα-dependent genes. Our results demonstrated that IFI27/ISG12 overexpression in MCF-7 cells reduced their proliferation rate in 2-D and 3-D cell culture assays and impaired their ability to migrate in a wound-healing assay. We show that IFI27/ISG12 downregulation of ERα transactivation activity is mediated by its ability to facilitate the interaction between ERα and CRM1/XPO1 that mediates the nuclear export of large macromolecules to the cytoplasm. IFI27/ISG12 overexpression was shown to impair the estradiol-dependent proliferation and tamoxifen-induced apoptosis in breast cancer cells. Our results suggest that IFI27/ISG12 may be an important factor in regulating ERα activity in breast cancer cells by modifying its nuclear versus cytoplasmic protein levels. We propose that IFI27/ISG12 may be a potential target of future strategies to control the growth and proliferation of ERα-positive breast cancer tumors.
Collapse
Affiliation(s)
- Mayte Guadalupe Cervantes-Badillo
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Alejandro Paredes-Villa
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Vania Gómez-Romero
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Rafael Cervantes-Roldán
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Luis E. Arias-Romero
- Unidad de Investigación en Biomedicina (UBIMED), Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Olga Villamar-Cruz
- Unidad de Investigación en Biomedicina (UBIMED), Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Miroslava González-Montiel
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Tonatiuh Barrios-García
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Alberto J. Cabrera-Quintero
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Ciudad de México, Mexico
| | - Gabriel Rodríguez-Gómez
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Laura Cancino-Villeda
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Alejandro Zentella-Dehesa
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Ciudad de México, Mexico
| | - Alfonso León-Del-Río
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| |
Collapse
|
|
32
|
Yokoo H, Ohoka N, Naito M, Demizu Y. Design and synthesis of peptide-based chimeric molecules to induce degradation of the estrogen and androgen receptors. Bioorg Med Chem 2020; 28:115595. [PMID: 32631565 DOI: 10.1016/j.bmc.2020.115595] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/05/2020] [Accepted: 06/08/2020] [Indexed: 01/12/2023]
Abstract
Peptide-based inducers of estrogen receptor (ER) α and androgen receptor (AR) degradations via the ubiquitin-proteasome system (UPS) were developed. The designated inducers were composed of two biologically active scaffolds: the helical peptide PERM3, which is an LXXLL-like mimic of the coactivator SRC-1, and various small molecules (MV1, LCL161, VH032, and POM) that bind to E3 ligases (IAPs, VHL, and cereblon, respectively), to induce ubiquitylation of nuclear receptors that bind to SRC-1. All of the synthesized chimeric E3 ligand-containing molecules induced the UPS-mediated degradation of ERα and AR. The PERM3 peptide was applicable for the development of the ERα and AR degraders using these E3 ligands.
Collapse
Affiliation(s)
- Hidetomo Yokoo
- National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medical Health Sciences, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan
| | - Nobumichi Ohoka
- National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan
| | - Mikihiko Naito
- National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan
| | - Yosuke Demizu
- National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medical Health Sciences, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan.
| |
Collapse
|
|
33
|
Zhang P, Yang Y, Qian K, Li L, Zhang C, Fu X, Zhang X, Chen H, Liu Q, Cao S, Cui J. A novel tumor suppressor ZBTB1 regulates tamoxifen resistance and aerobic glycolysis through suppressing HER2 expression in breast cancer. J Biol Chem 2020; 295:14140-14152. [PMID: 32690611 DOI: 10.1074/jbc.ra119.010759] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 07/07/2020] [Indexed: 12/18/2022] Open
Abstract
Transcriptional repressor zinc finger and BTB domain containing 1 (ZBTB1) is required for DNA repair. Because DNA repair defects often underlie genome instability and tumorigenesis, we determined to study the role of ZBTB1 in cancer. In this study, we found that ZBTB1 is down-regulated in breast cancer and this down-regulation is associated with poor outcome of breast cancer patients. ZBTB1 suppresses breast cancer cell proliferation and tumor growth. The majority of breast cancers are estrogen receptor (ER) positive and selective estrogen receptor modulators such as tamoxifen have been widely used in the treatment of these patients. Unfortunately, many patients develop resistance to endocrine therapy. Tamoxifen-resistant cancer cells often exhibit higher HER2 expression and an increase of glycolysis. Our data revealed that ZBTB1 plays a critical role in tamoxifen resistance in vitro and in vivo To see if ZBTB1 regulates HER2 expression, we tested the recruitments of ZBTB1 on HER2 regulatory sequences. We observed that over-expressed ZBTB1 occupies the estrogen receptor α (ERα)-binding site of the HER2 intron in tamoxifen-resistant cells, suppressing tamoxifen-induced transcription. In an effort to identify potential microRNAs (miRNAs) regulating ZBTB1, we found that miR-23b-3p directly targets ZBTB1. MiR-23b-3p regulates HER2 expression and tamoxifen resistance via targeting ZBTB1. Finally, we found that miR-23b-3p/ZBTB1 regulates aerobic glycolysis in tamoxifen-resistant cells. Together, our data demonstrate that ZBTB1 is a tumor suppressor in breast cancer cells and that targeting the miR-23b-3p/ZBTB1 may serve as a potential therapeutic approach for the treatment of tamoxifen resistant breast cancer.
Collapse
Affiliation(s)
- Panhong Zhang
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| | - Yutao Yang
- Department of Neurobiology, Capital Medical University, Beijing, P.R. China
| | - Kai Qian
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| | - Lianlian Li
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| | - Cuiping Zhang
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA
| | - Xiaoyi Fu
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China.,Department of Pathology, 2nd Affiliated Hospital, Yichun University, Yichun, Jiangxi, P.R. China
| | - Xiumei Zhang
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| | - Huan Chen
- Department of Pathology, The 1st affiliated Hospital, Yichun University, Yichun, Jiangxi, P.R. China
| | - Qiongqing Liu
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| | - Shengnan Cao
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| | - Jiajun Cui
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| |
Collapse
|
|
34
|
Byun JS, Singhal SK, Park S, Yi DI, Yan T, Caban A, Jones A, Mukhopadhyay P, Gil SM, Hewitt SM, Newman L, Davis MB, Jenkins BD, Sepulveda JL, De Siervi A, Nápoles AM, Vohra NA, Gardner K. Racial Differences in the Association Between Luminal Master Regulator Gene Expression Levels and Breast Cancer Survival. Clin Cancer Res 2020; 26:1905-1914. [PMID: 31911546 PMCID: PMC8051554 DOI: 10.1158/1078-0432.ccr-19-0875] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 07/10/2019] [Accepted: 01/03/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Compared with their European American (EA) counterparts, African American (AA) women are more likely to die from breast cancer in the United States. This disparity is greatest in hormone receptor-positive subtypes. Here we uncover biological factors underlying this disparity by comparing functional expression and prognostic significance of master transcriptional regulators of luminal differentiation. EXPERIMENTAL DESIGN Data and biospecimens from 262 AA and 293 EA patients diagnosed with breast cancer from 2001 to 2010 at a major medical center were analyzed by IHC for functional biomarkers of luminal differentiation, including estrogen receptor (ESR1) and its pioneer factors, FOXA1 and GATA3. Integrated comparison of protein levels with network-level gene expression analysis uncovered predictive correlations with race and survival. RESULTS Univariate or multivariate HRs for overall survival, estimated from digital IHC scoring of nuclear antigen, show distinct differences in the magnitude and significance of these biomarkers to predict survival based on race: ESR1 [EA HR = 0.47; 95% confidence interval (CI), 0.31-0.72 and AA HR = 0.77; 95% CI, 0.48-1.18]; FOXA1 (EA HR = 0.38; 95% CI, 0.23-0.63 and AA HR = 0.53; 95% CI, 0.31-0.88), and GATA3 (EA HR = 0.36; 95% CI, 0.23-0.56; AA HR = 0.57; CI, 0.56-1.4). In addition, we identify genes in the downstream regulons of these biomarkers highly correlated with race and survival. CONCLUSIONS Even within clinically homogeneous tumor groups, regulatory networks that drive mammary luminal differentiation reveal race-specific differences in their association with clinical outcome. Understanding these biomarkers and their downstream regulons will elucidate the intrinsic mechanisms that drive racial disparities in breast cancer survival.
Collapse
Affiliation(s)
- Jung S Byun
- National Institutes of Minority Health and Health Disparities, NIH, Bethesda, Maryland
| | - Sandeep K Singhal
- Columbia University Medical Center, Columbia University, New York, New York
| | - Samson Park
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Dae Ik Yi
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Tingfen Yan
- National Institutes of Minority Health and Health Disparities, NIH, Bethesda, Maryland
| | - Ambar Caban
- Columbia University Medical Center, Columbia University, New York, New York
| | - Alana Jones
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | | | - Sara M Gil
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stephen M Hewitt
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | | | | | | | - Jorge L Sepulveda
- Columbia University Medical Center, Columbia University, New York, New York
| | - Adriana De Siervi
- Laboratorio de Oncologıa Molecular y Nuevos Blancos Terapeuticos, Instituto de Biologıa y Medicina Experimental (IBYME), CONICET, Argentina
| | - Anna María Nápoles
- National Institutes of Minority Health and Health Disparities, NIH, Bethesda, Maryland
| | - Nasreen A Vohra
- Brody School of Medicine, East Carolina University, Greenville, North Carolina
| | - Kevin Gardner
- Columbia University Medical Center, Columbia University, New York, New York.
| |
Collapse
|
|
35
|
Moustaqil M, Gambin Y, Sierecki E. Biophysical Techniques for Target Validation and Drug Discovery in Transcription-Targeted Therapy. Int J Mol Sci 2020; 21:E2301. [PMID: 32225120 PMCID: PMC7178067 DOI: 10.3390/ijms21072301] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/13/2020] [Accepted: 03/13/2020] [Indexed: 01/10/2023] Open
Abstract
In the post-genome era, pathologies become associated with specific gene expression profiles and defined molecular lesions can be identified. The traditional therapeutic strategy is to block the identified aberrant biochemical activity. However, an attractive alternative could aim at antagonizing key transcriptional events underlying the pathogenesis, thereby blocking the consequences of a disorder, irrespective of the original biochemical nature. This approach, called transcription therapy, is now rendered possible by major advances in biophysical technologies. In the last two decades, techniques have evolved to become key components of drug discovery platforms, within pharmaceutical companies as well as academic laboratories. This review outlines the current biophysical strategies for transcription manipulation and provides examples of successful applications. It also provides insights into the future development of biophysical methods in drug discovery and personalized medicine.
Collapse
Affiliation(s)
- Mehdi Moustaqil
- EMBL Australia Node in Single Molecule Science and School of Medical Sciences, UNSW Sydney, NSW 2052, Australia;
| | | | - Emma Sierecki
- EMBL Australia Node in Single Molecule Science and School of Medical Sciences, UNSW Sydney, NSW 2052, Australia;
| |
Collapse
|
|
36
|
Stossi F, Dandekar RD, Mancini MG, Gu G, Fuqua SAW, Nardone A, De Angelis C, Fu X, Schiff R, Bedford MT, Xu W, Johansson HE, Stephan CC, Mancini MA. Estrogen-induced transcription at individual alleles is independent of receptor level and active conformation but can be modulated by coactivators activity. Nucleic Acids Res 2020; 48:1800-1810. [PMID: 31930333 PMCID: PMC7039002 DOI: 10.1093/nar/gkz1172] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 11/29/2019] [Accepted: 12/06/2019] [Indexed: 12/23/2022] Open
Abstract
Steroid hormones are pivotal modulators of pathophysiological processes in many organs, where they interact with nuclear receptors to regulate gene transcription. However, our understanding of hormone action at the single cell level remains incomplete. Here, we focused on estrogen stimulation of the well-characterized GREB1 and MYC target genes that revealed large differences in cell-by-cell responses, and, more interestingly, between alleles within the same cell, both over time and hormone concentration. We specifically analyzed the role of receptor level and activity state during allele-by-allele regulation and found that neither receptor level nor activation status are the determinant of maximal hormonal response, indicating that additional pathways are potentially in place to modulate cell- and allele-specific responses. Interestingly, we found that a small molecule inhibitor of the arginine methyltransferases CARM1 and PRMT6 was able to increase, in a gene specific manner, the number of active alleles/cell before and after hormonal stimulation, suggesting that mechanisms do indeed exist to modulate hormone receptor responses at the single cell and allele level.
Collapse
Affiliation(s)
- Fabio Stossi
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Integrated Microscopy Core, Baylor College of Medicine, Houston, TX 77030, USA
- Gulf Coast Consortia Center for Advanced Microscopy and Image Informatics, Houston, TX 77030, USA
| | - Radhika D Dandekar
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Integrated Microscopy Core, Baylor College of Medicine, Houston, TX 77030, USA
| | - Maureen G Mancini
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Gulf Coast Consortia Center for Advanced Microscopy and Image Informatics, Houston, TX 77030, USA
| | - Guowei Gu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Suzanne A W Fuqua
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Agostina Nardone
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Carmine De Angelis
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xiaoyong Fu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Rachel Schiff
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mark T Bedford
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Wei Xu
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | | | - Clifford C Stephan
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA
| | - Michael A Mancini
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Integrated Microscopy Core, Baylor College of Medicine, Houston, TX 77030, USA
- Gulf Coast Consortia Center for Advanced Microscopy and Image Informatics, Houston, TX 77030, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA
| |
Collapse
|
|
37
|
Si W, Zhou J, Zhao Y, Zheng J, Cui L. SET7/9 promotes multiple malignant processes in breast cancer development via RUNX2 activation and is negatively regulated by TRIM21. Cell Death Dis 2020; 11:151. [PMID: 32102992 PMCID: PMC7044199 DOI: 10.1038/s41419-020-2350-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 02/08/2020] [Accepted: 02/10/2020] [Indexed: 12/21/2022]
Abstract
Although the deregulation of lysine methyltransferase (su(var)-3-9, enhancer-of-zeste, trithorax) domain-containing protein 7/9 (SET7/9) has been identified in a variety of cancers, the potential role of SET7/9 and the molecular events in which it is involved in breast cancer remain obscure. Using the online Human Protein Atlas and GEO databases, the expression of SET7/9 was analyzed. Furthermore, we investigated the underlying mechanisms using chromatin immunoprecipitation-based deep sequencing (ChIP-seq) and quantitative ChIP assays. To explore the physiological role of SET7/9, functional analyses such as CCK-8, colony formation, and transwell assays were performed and a xenograft tumor model was generated with the human breast cancer cell lines MCF-7 and MDA-MB-231. Mass spectrometry, co-immunoprecipitation, GST pull-down, and ubiquitination assays were used to explore the mechanisms of SET7/9 function in breast cancer. We evaluated the expression of SET7/9 in different breast cancer cohorts and found that higher expression indicated worse survival times in these public databases. We demonstrated positive effects of SET7/9 on cell proliferation, migration, and invasion via the activation of Runt-related transcription factor 2 (RUNX2). We demonstrate that tripartite motif-containing protein 21 (TRIM21) physically associates with SET7/9 and functions as a major negative regulator upstream of SET7/9 through a proteasome-dependent mechanism and increased ubiquitination. Taken together, our data suggest that SET7/9 has a promoting role via the regulation of RUNX2, whereas TRIM21-mediated SET7/9 degradation acts as an anti-braking system in the progression of breast cancer.
Collapse
Affiliation(s)
- Wenzhe Si
- Department of Laboratory Medicine, Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China.
| | - Jiansuo Zhou
- Department of Laboratory Medicine, Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China
| | - Yang Zhao
- Department of Laboratory Medicine, Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China
| | - Jiajia Zheng
- Department of Laboratory Medicine, Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China
| | - Liyan Cui
- Department of Laboratory Medicine, Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China.
| |
Collapse
|
|
38
|
Chen R, Guo S, Yang C, Sun L, Zong B, Li K, Liu L, Tu G, Liu M, Liu S. Although c‑MYC contributes to tamoxifen resistance, it improves cisplatin sensitivity in ER‑positive breast cancer. Int J Oncol 2020; 56:932-944. [PMID: 32319562 PMCID: PMC7050981 DOI: 10.3892/ijo.2020.4987] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 01/24/2020] [Indexed: 12/19/2022] Open
Abstract
Tamoxifen (TAM) resistance is a major challenge in the treatment of estrogen receptor‑positive (ER+) breast cancer. To date, to the best of our knowledge, there are only a few studies available examining the response of patients with TAM‑resistant breast cancer to chemotherapy, and the guidelines do not specify recommended drugs for these patients. In the present study, TAM‑resistant cells were shown to exhibit increased proliferation and invasion compared with the parent cells, and the increased expression of c‑MYC was demonstrated to play an important role in TAM resistance. Furthermore, the TAM‑resistant cells were significantly more sensitive to cisplatin compared with the parent cells, and the silencing of c‑MYC expression desensitized the cells to cisplatin through the inhibition of the cell cycle. An increased c‑MYC expression was observed in 28 pairs of primary and metastatic tumors from patients treated with TAM, and the clinical remission rate of cisplatin‑based chemotherapy was significantly higher compared with other chemotherapy‑based regimens in 122 patients with TAM resistant breast cancer. Taken together, the data of the present study demonstrated that although c‑MYC was involved in TAM resistance, it increased the sensitivity of ER+ breast cancer to cisplatin. Thus, cisplatin may be a preferred chemotherapeutic agent for the treatment of patients with TAM‑resistant breast cancer, particularly in patients where the rapid control of disease progression is required.
Collapse
Affiliation(s)
- Rui Chen
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Shipeng Guo
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Chengcheng Yang
- Department of Breast Surgery, The People's Hospital of Deyang, Deyang, Sichuan 618000, P.R. China
| | - Lu Sun
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Beige Zong
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Kang Li
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Li Liu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Gang Tu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Manran Liu
- Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Shengchun Liu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| |
Collapse
|
|
39
|
Zhou Z, Xu B, Minn A, Zhang NR. DENDRO: genetic heterogeneity profiling and subclone detection by single-cell RNA sequencing. Genome Biol 2020; 21:10. [PMID: 31937348 PMCID: PMC6961311 DOI: 10.1186/s13059-019-1922-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 12/16/2019] [Indexed: 12/18/2022] Open
Abstract
Although scRNA-seq is now ubiquitously adopted in studies of intratumor heterogeneity, detection of somatic mutations and inference of clonal membership from scRNA-seq is currently unreliable. We propose DENDRO, an analysis method for scRNA-seq data that clusters single cells into genetically distinct subclones and reconstructs the phylogenetic tree relating the subclones. DENDRO utilizes transcribed point mutations and accounts for technical noise and expression stochasticity. We benchmark DENDRO and demonstrate its application on simulation data and real data from three cancer types. In particular, on a mouse melanoma model in response to immunotherapy, DENDRO delineates the role of neoantigens in treatment response.
Collapse
Affiliation(s)
- Zilu Zhou
- Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, PA USA
- Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA USA
| | - Bihui Xu
- Department of Radiation Oncology, Parker Institute for Cancer Immunotherapy, Abramson Family Cancer Research Institute, Graduate Group in Cell and Molecular Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Andy Minn
- Department of Radiation Oncology, Parker Institute for Cancer Immunotherapy, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Nancy R. Zhang
- Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA USA
| |
Collapse
|
|
40
|
ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer. Nat Genet 2020; 52:198-207. [PMID: 31932695 DOI: 10.1038/s41588-019-0554-0] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 11/21/2019] [Indexed: 12/14/2022]
Abstract
Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, are the most common alterations of the SWI/SNF complex in estrogen-receptor-positive (ER+) breast cancer. We identify that ARID1A inactivating mutations are present at a high frequency in advanced endocrine-resistant ER+ breast cancer. An epigenome CRISPR-CAS9 knockout (KO) screen identifies ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A inactivation in cells and in patients leads to resistance to ER degraders by facilitating a switch from ER-dependent luminal cells to ER-independent basal-like cells. Cellular plasticity is mediated by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the luminal lineage-determining transcription factors including ER, forkhead box protein A1 (FOXA1) and GATA-binding factor 3 (GATA3). ARID1A also regulates genome-wide ER-FOXA1 chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in maintaining luminal cell identity and endocrine therapeutic response in ER+ breast cancer.
Collapse
|
|
41
|
Abstract
One of the hallmarks of hormone receptor (HR)-positive breast cancer is its dependence on the phosphatidylinositol-3-kinase (PI3K) pathway. Here, we review the epidemiologic, functional, and pharmacologic interactions between oncogenic PI3K and the estrogen receptor (ER). We discuss the epidemiology of PI3K pathway alterations, mechanisms of resistance to PI3K inhibitors, and the current mechanistic landscape of crosstalk between PI3K and ER, which provide the rationale for dual ER and PI3K inhibition and is now a standard of care in the treatment of ER+ PIK3CA-mutant metastatic breast cancer. We outline newer studies in this field that delineate the clinically relevant overlaps between PI3K and parallel signaling pathways, insulin signaling, and ER epigenetic modifiers. We also identify several caveats with the current data and propose new strategies to overcome these bottlenecks.
Collapse
Affiliation(s)
- N Vasan
- Human Oncology and Pathogenesis Program, New York, USA
- Departments of Medicine, New York, USA
| | - E Toska
- Human Oncology and Pathogenesis Program, New York, USA
| | - M Scaltriti
- Human Oncology and Pathogenesis Program, New York, USA
- Departments of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA
| |
Collapse
|
|
42
|
Tang ZR, Zhang R, Lian ZX, Deng SL, Yu K. Estrogen-Receptor Expression and Function in Female Reproductive Disease. Cells 2019; 8:E1123. [PMID: 31546660 PMCID: PMC6830311 DOI: 10.3390/cells8101123] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/20/2019] [Accepted: 09/20/2019] [Indexed: 01/13/2023] Open
Abstract
Estrogen receptors (ER) include ER alpha, ER beta and new membrane receptor G protein-coupled receptor 30 (GPR30). Estrogen receptors are key receptors to maintain ovarian granulosa cell differentiation, follicle and oocyte growth and development, and ovulation function. The abnormal functions of estrogen, its receptors, and estradiol synthesis-related enzymes are closely related to clinical reproductive endocrine diseases, such as polycystic ovary syndrome (PCOS) and endometriosis (EMS). At present, hormone therapy is the main treatment for ovarian-related diseases, and a stable hormone environment is established by regulating ovarian function. In recent years, some estrogen-related drugs have made great progress, such as clomiphene, which is a nonsteroidal antiestrogen drug in clinical application. This article elaborates on the regulatory role of estrogen and its nuclear receptors and membrane receptors in oocyte development, especially female reproductive diseases related to the abnormal expression of estrogen and its receptors. We also highlighted the latest advances of treatment strategy for these diseases and the application of related targeted small molecule drugs in clinical research and treatment, so as to provide reference for the treatment of female reproductive diseases.
Collapse
Affiliation(s)
- Zi-Run Tang
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
| | - Rui Zhang
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
| | - Zheng-Xing Lian
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
| | - Shou-Long Deng
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
| | - Kun Yu
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
| |
Collapse
|
|
43
|
Nassa G, Giurato G, Salvati A, Gigantino V, Pecoraro G, Lamberti J, Rizzo F, Nyman TA, Tarallo R, Weisz A. The RNA-mediated estrogen receptor α interactome of hormone-dependent human breast cancer cell nuclei. Sci Data 2019; 6:173. [PMID: 31527615 PMCID: PMC6746822 DOI: 10.1038/s41597-019-0179-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 07/25/2019] [Indexed: 01/11/2023] Open
Abstract
Estrogen Receptor alpha (ERα) is a ligand-inducible transcription factor that mediates estrogen signaling in hormone-responsive cells, where it controls key cellular functions by assembling in gene-regulatory multiprotein complexes. For this reason, interaction proteomics has been shown to represent a useful tool to investigate the molecular mechanisms underlying ERα action in target cells. RNAs have emerged as bridging molecules, involved in both assembly and activity of transcription regulatory protein complexes. By applying Tandem Affinity Purification (TAP) coupled to mass spectrometry (MS) before and after RNase digestion in vitro, we generated a dataset of nuclear ERα molecular partners whose association with the receptor involves RNAs. These data provide a useful resource to elucidate the combined role of nuclear RNAs and the proteins identified here in ERα signaling to the genome in breast cancer and other cell types.
Collapse
Affiliation(s)
- Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy
- Genomix4Life srl, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Baronissi, SA, Italy
| | - Annamaria Salvati
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy
| | - Valerio Gigantino
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy
| | - Giovanni Pecoraro
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy
| | - Jessica Lamberti
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy
| | - Tuula A Nyman
- Department of Immunology, Institute of Clinical Medicine, University of Oslo and Rikshospitalet Oslo, 0372, Oslo, Norway
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy.
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy.
| |
Collapse
|
|
44
|
Castel P, Toska E. Chromatin regulation at the intersection of estrogen receptor and PI3K pathways in breast cancer. Mol Cell Oncol 2019; 6:e1625620. [PMID: 31692833 PMCID: PMC6816426 DOI: 10.1080/23723556.2019.1625620] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 05/22/2019] [Accepted: 05/28/2019] [Indexed: 11/11/2022]
Abstract
Estrogen Receptor (ER) and the phosphoinositide 3-kinase (PI3K) pathways participate in regulatory crosstalk in breast cancer. We identified that chromatin regulation is at the intersection of oncogenic PI3K and ER. The PI3K effectors AKT, also known as protein kinase B (PKB), and SGK (serum/glucocorticoid-regulated kinase) play a redundant role by phosphorylating the chromatin regulator KMT2D and modulating ER activity and therapy resistance.
Collapse
Affiliation(s)
- Pau Castel
- Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Eneda Toska
- Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY, USA
| |
Collapse
|
|
45
|
Jones D, Wilson L, Thomas H, Gaughan L, Wade MA. The Histone Demethylase Enzymes KDM3A and KDM4B Co-Operatively Regulate Chromatin Transactions of the Estrogen Receptor in Breast Cancer. Cancers (Basel) 2019; 11:cancers11081122. [PMID: 31390833 PMCID: PMC6721541 DOI: 10.3390/cancers11081122] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/29/2019] [Accepted: 08/03/2019] [Indexed: 02/07/2023] Open
Abstract
Many estrogen receptor (ER)-positive breast cancers develop resistance to endocrine therapy but retain canonical receptor signalling in the presence of selective ER antagonists. Numerous co-regulatory proteins, including enzymes that modulate the chromatin environment, control the transcriptional activity of the ER. Targeting ER co-regulators has therefore been proposed as a novel therapeutic approach. By assessing DNA-binding dynamics in ER-positive breast cancer cells, we have identified that the histone H3 lysine 9 demethylase enzymes, KDM3A and KDM4B, co-operate to regulate ER activity via an auto-regulatory loop that facilitates the recruitment of each co-activating enzyme to chromatin. We also provide evidence that suggests that KDM3A primes chromatin for deposition of the ER pioneer factor FOXA1 and recruitment of the ER-transcriptional complex, all prior to ER recruitment, therefore establishing an important mechanism of chromatin regulation involving histone demethylases and pioneer factors, which controls ER functionality. Importantly, we show via global gene-expression analysis that a KDM3A/KDM4B/FOXA1 co-regulated gene signature is enriched for pro-proliferative and ER-target gene sets, suggesting that abrogation of this network could be an efficacious therapeutic strategy. Finally, we show that depletion of both KDM3A and KDM4B has a greater inhibitory effect on ER activity and cell growth than knockdown of each individual enzyme, suggesting that targeting both enzymes represents a potentially efficacious therapeutic option for ER-driven breast cancer.
Collapse
Affiliation(s)
- Dominic Jones
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Laura Wilson
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Huw Thomas
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Luke Gaughan
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Mark A Wade
- Biomedical Sciences, Faculty of Health Sciences, University of Hull, Hull HU6 7RX, UK.
| |
Collapse
|
|
46
|
Zhang X, Zhang B, Zhang P, Lian L, Li L, Qiu Z, Qian K, Chen A, Liu Q, Jiang Y, Cui J, Qi B. Norcantharidin regulates ERα signaling and tamoxifen resistance via targeting miR-873/CDK3 in breast cancer cells. PLoS One 2019; 14:e0217181. [PMID: 31120927 PMCID: PMC6532885 DOI: 10.1371/journal.pone.0217181] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 05/07/2019] [Indexed: 12/11/2022] Open
Abstract
MiR-873/CDK3 has been shown to play a critical role in ERα signaling and tamoxifen resistance. Thus, targeting this pathway may be a potential therapeutic approach for the treatment of ER positive breast cancer especially tamoxifen resistant subtype. Here we report that Norcantharidin (NCTD), currently used clinically as an ani-cancer drug in China, regulates miR-873/CDK3 axis in breast cancer cells. NCTD decreases the transcriptional activity of ERα but not ERβ through the modulation of miR-873/CDK3 axis. We also found that NCTD inhibits cell proliferation and tumor growth and miR-873/CDK3 axis mediates cell proliferation suppression of NCTD. More important, we found that NCTD sensitizes resistant cells to tamoxifen. NCTD inhibits tamoxifen induced the transcriptional activity as well ERα downstream gene expressions in tamoxifen resistant breast cancer cells. In addition, we found that NCTD restores tamoxifen induced recruitments of ERα co-repressors N-CoR and SMRT. Knockdown of miR-873 and overexpression of CDK3 diminish the effect of NCTD on tamoxifen resistance. Our data shows that NCTD regulates ERα signaling and tamoxifen resistance by targeting miR-873/CDK3 axis in breast cancer cells. This study may provide an alternative therapy strategy for tamoxifen resistant breast cancer.
Collapse
Affiliation(s)
- Xiumei Zhang
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
- College of Chemistry and Bio-engineering, Yichun University, Yichun, Jiangxi, P.R. China
| | - Bingfeng Zhang
- College of Chemistry and Bio-engineering, Yichun University, Yichun, Jiangxi, P.R. China
| | - Panhong Zhang
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
- College of Chemistry and Bio-engineering, Yichun University, Yichun, Jiangxi, P.R. China
| | - Lihui Lian
- Department of Cell Biology, College of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, P.R. China
| | - Lianlian Li
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| | - Zhihong Qiu
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| | - Kai Qian
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| | - An Chen
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| | - Qiongqing Liu
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
- College of Chemistry and Bio-engineering, Yichun University, Yichun, Jiangxi, P.R. China
| | - Yinjie Jiang
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
| | - Jiajun Cui
- The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China
- * E-mail: (JC); (BQ)
| | - Bing Qi
- Department of Cell Biology, College of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, P.R. China
- * E-mail: (JC); (BQ)
| |
Collapse
|
|
47
|
Holding AN, Giorgi FM, Donnelly A, Cullen AE, Nagarajan S, Selth LA, Markowetz F. VULCAN integrates ChIP-seq with patient-derived co-expression networks to identify GRHL2 as a key co-regulator of ERa at enhancers in breast cancer. Genome Biol 2019; 20:91. [PMID: 31084623 PMCID: PMC6515683 DOI: 10.1186/s13059-019-1698-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND VirtUaL ChIP-seq Analysis through Networks (VULCAN) infers regulatory interactions of transcription factors by overlaying networks generated from publicly available tumor expression data onto ChIP-seq data. We apply our method to dissect the regulation of estrogen receptor-alpha activation in breast cancer to identify potential co-regulators of the estrogen receptor's transcriptional response. RESULTS VULCAN analysis of estrogen receptor activation in breast cancer highlights the key components of the estrogen receptor complex alongside a novel interaction with GRHL2. We demonstrate that GRHL2 is recruited to a subset of estrogen receptor binding sites and regulates transcriptional output, as evidenced by changes in estrogen receptor-associated eRNA expression and stronger estrogen receptor binding at active enhancers after GRHL2 knockdown. CONCLUSIONS Our findings provide new insight into the role of GRHL2 in regulating eRNA transcription as part of estrogen receptor signaling. These results demonstrate VULCAN, available from Bioconductor, as a powerful predictive tool.
Collapse
Affiliation(s)
- Andrew N Holding
- CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK.
- The Alan Turing Institute, 96 Euston Road, Kings Cross, London, NW1 2DB, UK.
| | - Federico M Giorgi
- CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
- Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, Bologna, Italy
| | - Amanda Donnelly
- CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
| | - Amy E Cullen
- CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
| | - Sankari Nagarajan
- CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
| | - Luke A Selth
- Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Florian Markowetz
- CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
| |
Collapse
|
|
48
|
Shibata T, Tokunaga E, Hattori S, Watari K, Murakami Y, Yamashita N, Oki E, Itou J, Toi M, Maehara Y, Kuwano M, Ono M. Y-box binding protein YBX1 and its correlated genes as biomarkers for poor outcomes in patients with breast cancer. Oncotarget 2018; 9:37216-37228. [PMID: 30647855 PMCID: PMC6324687 DOI: 10.18632/oncotarget.26469] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 12/05/2018] [Indexed: 01/10/2023] Open
Abstract
The enhanced expression of the Y-box binding protein YBX1 is consistently correlated with poor outcomes or reduced survival of breast cancer patients. However, the mechanism underlying the association between increased YBX1 expression and poor outcomes has yet to be revealed. We searched a database for the top 500 genes that are positively or negatively correlated with YBX1 and with ESR1 in breast cancer patients. We further examined the association between YBX1-correlated genes and breast cancer outcomes in patients at Kyushu University Hospital. More than 60% of genes that are positively correlated with YBX1 are also negatively correlated with ESR1. The enhanced expression levels of the top 20 positively correlated genes mostly predict negative outcomes, while the enhanced expression levels of the top 20 negatively correlated genes mostly predict positive outcomes. Furthermore, in breast cancer patients at Kyushu University Hospital, the expression levels of YBX1 and YBX1-positively correlated genes were significantly higher and the expression levels of genes negatively correlated with YBX1 were significantly lower in patients who relapsed after their primary surgery than in those who did not relapse. The expression of YBX1 together with the expression of its positively or negatively correlated genes may help to predict outcomes as well as resistance to endocrine therapies in breast cancer patients. Determining the expression of YBX1 and its closely correlated genes will contribute to the development of precision therapeutics for breast cancer.
Collapse
Affiliation(s)
- Tomohiro Shibata
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Eriko Tokunaga
- National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Satoshi Hattori
- Department of Integrated Medicine, Biomedical Statistics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kosuke Watari
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuichi Murakami
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.,Cancer Translational Research Center, St. Mary's Institute of Health Sciences, Kurume, Japan
| | - Nami Yamashita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Junji Itou
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masakazu Toi
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihiko Maehara
- Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan
| | - Michihiko Kuwano
- Cancer Translational Research Center, St. Mary's Institute of Health Sciences, Kurume, Japan
| | - Mayumi Ono
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| |
Collapse
|
|
49
|
Wang S, Li X, Zhang W, Gao Y, Zhang K, Hao Q, Li W, Wang Z, Li M, Zhang W, Zhang Y, Zhang C. Genome-Wide Investigation of Genes Regulated by ERα in Breast Cancer Cells. Molecules 2018; 23:molecules23102543. [PMID: 30301189 PMCID: PMC6222792 DOI: 10.3390/molecules23102543] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 09/26/2018] [Accepted: 10/03/2018] [Indexed: 01/13/2023] Open
Abstract
Estrogen receptor alpha (ERα), which has been detected in over 70% of breast cancer cases, is a driving factor for breast cancer growth. For investigating the underlying genes and networks regulated by ERα in breast cancer, RNA-seq was performed between ERα transgenic MDA-MB-231 cells and wild type MDA-MB-231 cells. A total of 267 differentially expressed genes (DEGs) were identified. Then bioinformatics analyses were performed to illustrate the mechanism of ERα. Besides, by comparison of RNA-seq data obtained from MDA-MB-231 cells and microarray dataset obtained from estrogen (E2) stimulated MCF-7 cells, an overlap of 126 DEGs was screened. The expression level of ERα was negatively associated with metastasis and EMT in breast cancer. We further verified that ERα might inhibit metastasis by regulating of VCL and TNFRSF12A, and suppress EMT by the regulating of JUNB and ID3. And the relationship between ERα and these genes were validated by RT-PCR and correlation analysis based on TCGA database. By PPI network analysis, we identified TOP5 hub genes, FOS, SP1, CDKN1A, CALCR and JUNB, which were involved in cell proliferation and invasion. Taken together, the whole-genome insights carried in this work can help fully understanding biological roles of ERα in breast cancer.
Collapse
Affiliation(s)
- Shuning Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| | - Xiaoju Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| | - Yuan Gao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| | - Kuo Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| | - Weina Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| | - Zhaowei Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| | - Meng Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
| |
Collapse
|
|
50
|
Bemanian V, Noone JC, Sauer T, Touma J, Vetvik K, Søderberg-Naucler C, Lindstrøm JC, Bukholm IR, Kristensen VN, Geisler J. Somatic EP300-G211S mutations are associated with overall somatic mutational patterns and breast cancer specific survival in triple-negative breast cancer. Breast Cancer Res Treat 2018; 172:339-351. [PMID: 30132219 DOI: 10.1007/s10549-018-4927-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 08/17/2018] [Indexed: 10/28/2022]
Abstract
PURPOSE We have compared the mutational profiles of human breast cancer tumor samples belonging to all major subgroups with special emphasis on triple-negative breast cancer (TNBC). Our major goal was to identify specific mutations that could be potentially used for clinical decision making in TNBC patients. PATIENTS AND METHODS Primary tumor specimens from 149 Norwegian breast cancer patients were available. We analyzed the tissue samples for somatic mutations in 44 relevant breast cancer genes by targeted next-generation sequencing. As a second confirmatory technique, we performed pyrosequencing on selected samples. RESULTS We observed a distinct subgroup of TNBC patients, characterized by an almost completely lack of pathogenic somatic mutations. A point mutation in the adenoviral E1A binding protein p300 (EP300-G211S) was significantly correlated to this TNBC subgroup. The EP300-G211S mutation was exclusively found in the TNBC patients and its presence reduced the chance for other pathological somatic mutations in typical breast cancer genes investigated in our gene panel by 94.9% (P < 0.005). Interestingly, the EP300-G211S mutation also predicted a lower risk for relapses and decreased breast cancer-specific mortality during long-term follow-up of the patients. CONCLUSION Next-generation sequencing revealed specific mutations in EP300 to be associated with the mutational patterns in typical breast cancer genes and long-term outcome of triple-negative breast cancer patients.
Collapse
Affiliation(s)
- Vahid Bemanian
- Section of Gene Technology, Akershus University Hospital, 1478, Lørenskog, Norway
| | | | - Torill Sauer
- Department of Pathology, Akershus University Hospital, 1478, Lørenskog, Norway.,Institute of Clinical Medicine, University of Oslo, Campus at Akershus University Hospital, 1478, Lørenskog, Norway
| | - Joel Touma
- Department of Breast and Endocrine Surgery, Akershus University Hospital, 1478, Lørenskog, Norway.,Department of Oncology, Akershus University Hospital, 1478, Lørenskog, Norway
| | - Katja Vetvik
- Institute of Clinical Medicine, University of Oslo, Campus at Akershus University Hospital, 1478, Lørenskog, Norway.,Department of Breast and Endocrine Surgery, Akershus University Hospital, 1478, Lørenskog, Norway
| | - Cecilia Søderberg-Naucler
- Department of Medicine at Solna, Experimental Cardiovascular Research Unit and Departments of Medicine and Neurology, Center for Molecular Medicine, Karolinska Institute, 17176, Stockholm, Sweden
| | - Jonas Christoffer Lindstrøm
- Institute of Clinical Medicine, University of Oslo, Campus at Akershus University Hospital, 1478, Lørenskog, Norway.,Health Services Research Unit, Akershus University Hospital, 1478, Lørenskog, Norway
| | - Ida Rashida Bukholm
- Department of Breast and Endocrine Surgery, Akershus University Hospital, 1478, Lørenskog, Norway.,Norwegian System of Compensation to Patients, Oslo, Norway.,The Norwegian University of Life Sciences, Ås, Norway
| | - Vessela N Kristensen
- Institute of Clinical Medicine, University of Oslo, Campus at Akershus University Hospital, 1478, Lørenskog, Norway.,Clinical Molecular Biology (EPIGEN), Akershus University Hospital, 1478, Lørenskog, Norway
| | - Jürgen Geisler
- Institute of Clinical Medicine, University of Oslo, Campus at Akershus University Hospital, 1478, Lørenskog, Norway. .,Department of Oncology, Akershus University Hospital, 1478, Lørenskog, Norway.
| |
Collapse
|