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Distinct Roles of BET Family Members in ERα Enhancer Function and Gene Regulation in Breast Cancer Cells [RNA-seq]

ABSTRACT: Estrogen (E2)-dependent gene regulation mediated by estrogen receptor alpha (ERα) plays a mitogenic role in ER-positive breast cancer cells. Although clinical applications of selective estrogen receptor modulators (SERMs), which directly interact with ERα to alter ERα activity, have been effective as a first line of treatment for breast cancer patients, a large subset of the patients will develop resistance after prolonged use of SERMs. Thus, there is a great need to develop alternative therapeutic strategies for SERM-resistant breast cancers. Here, we describe the potential use of the bromodomain family member protein (BRD) selective bromodomain inhibitor, JQ1, to alter E2-dependent gene expression program and inhibit E2-dependent growth of breast cancer cells. We show that each family member has partially redundant roles as ERα coregulators that are required for ERα-mediated gene transcription. Furthermore, we demonstrate the function of BRD3 as a molecular sensor of total BRD activity by the compensatory control of its protein levels. In addition, BRD3 colocalizes with a subset of ERα binding sites (ERBSs) that are enriched for active enhancer features and associated with highly E2-induced genes. Collectively, we illustrate a critical role of the BET family members in ERα dependent gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109570 | GEO | 2019/09/25

REPOSITORIES: GEO

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Distinct roles of BET Family Members in ERα Enhancer Function and Gene Regulation in Breast Cancer Cells [ChIP-seq]

Project description:Estrogen (E2)-dependent gene regulation mediated by estrogen receptor alpha (ERα) plays a mitogenic role in ER-positive breast cancer cells. Although clinical applications of selective estrogen receptor modulators (SERMs), which directly interact with ERα to alter ERα activity, have been effective as a first line of treatment for breast cancer patients, a large subset of the patients will develop resistance after prolonged use of SERMs. Thus, there is a great need to develop alternative therapeutic strategies for SERM-resistant breast cancers. Here, we describe the potential use of the bromodomain family member protein (BRD) selective bromodomain inhibitor, JQ1, to alter E2-dependent gene expression program and inhibit E2-dependent growth of breast cancer cells. We show that each family member has partially redundant roles as ERα coregulators that are required for ERα-mediated gene transcription. Furthermore, we demonstrate the function of BRD3 as a molecular sensor of total BRD activity by the compensatory control of its protein levels. In addition, BRD3 colocalizes with a subset of ERα binding sites (ERBSs) that are enriched for active enhancer features and associated with highly E2-induced genes. Collectively, we illustrate a critical role of the BET family members in ERα dependent gene expression.

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Project description:Estrogen receptor alpha (ERα)-positive breast cancers, while initially being responsive, eventually develop resistance to ERα targeted therapies through ERα-dependent and ERα-independent mechanisms. Through functional genomic studies we report heretofore unrecognized role for the axon guidance dependence receptor UNC5A in fine-tuning estradiol (E2) and anti-estrogen response. Knockdown of the estradiol-inducible UNC5A caused unrestricted ERα signaling as evident from deregulated E2-regulated gene expression and E2-independent tumorigenesis accompanied with multi-organ metastatic spread in xenograft models. UNC5A-knockdown cells displayed luminal/basal hybrid phenotype characterized by elevated expression of basal/stem cell enriched ∆Np63 and ITGA6 (CD49f), anti-apoptotic BCL2, and the lymphangiogenic factor NTN4 but lower expression of luminal/alveolar differentiation-associated factor ELF5 while maintaining functional ERα. Thus, UNC5A is a new regulator of ERα with a tumor/metastasis suppressive activity. Significance: ERα signaling network plays a significant role in ~70% of breast cancers. While the signaling molecules that partner with ERα to augment E2-dependent signaling and promote breast cancer progression have been well studied, negative feedback proteins that attenuate ERα signaling and their contribution to breast cancer progression are yet to be identified. This study reports E2-inducible UNC5A as a critical attenuator of ERα signaling and its reduced expression in primary breast cancer is associated with poor outcome. UNC5A potentially controls ERα signaling by restricting PI3K/AKT:ERα crosstalk needed for E2-independent activity while simultaneously maintaining ERα-dependent luminal differentiation program. These findings have important implications in developing strategies to combat anti-estrogen resistance and to improve clinical utility of PI3K/AKT inhibitors.

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Genome-wide mapping of ligand-dependent ERα binding sites in the ERα AF-2 mutant mouse uterus

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H4K12ac is regulated by estrogen receptor-alpha and is associated with BRD4 function and inducible transcription

Project description:Hormone-dependent gene expression requires dynamic and coordinated epigenetic changes. Estrogen receptor-positive (ER+) breast cancer is particularly dependent upon extensive chromatin remodeling and changes in histone modifications for the induction of hormone-responsive gene expression. Our previous studies established an important role of bromodomain-containing protein-4 (BRD4) in promoting estrogen-regulated transcription and proliferation of ER+ breast cancer cells. Here, we investigated the association between genome-wide occupancy of histone H4 acetylation at lysine 12 (H4K12ac) and BRD4 in the context of estrogen-induced transcription. Similar to BRD4, we observed that H4K12ac occupancy increases near the transcription start sites (TSS) of estrogen-induced genes as well as at distal ERα binding sites in an estrogen-dependent manner. Interestingly, H4K12ac occupancy highly correlates with BRD4 binding and enhancer RNA production on ERα-positive enhancers. Consistent with an importance in estrogen-induced gene transcription, H4K12ac occupancy globally increased in ER-positive cells relative to ER-negative cells and these levels were further increased by estrogen treatment in an ERα-dependent manner. Together, these findings reveal a strong correlation between H4K12ac and BRD4 occupancy with estrogen-dependent gene transcription and further suggest that modulators of H4K12ac and BRD4 may serve as new therapeutic targets for hormone-dependent cancers. ChIP-seq profiles of H4K12ac in MCF7 cells treated with +/- estrogen treatment and MCF10A cells.

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Project description:ERα17p is a synthetic peptide corresponding to the sequence P295LMIKRSKKNSLALSLT311 of the estrogen receptor alpha (ERα) and initially synthesized to mimic its calmodulin binding site. ERα17p was subsequently found to elicit estrogenic responses in E2-deprived ERα-positive breast cancer cells, increasing proliferation and E2-dependent gene transcription. Surprisingly, in E2-supplemented media, ERα17p induced apoptosis and modified the actin network, influencing thereby cell motility. Here, we report that ERα17p induces a massive early (3h) transcriptional activity in breast cancer cell line T47D.

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Time-course effect of estradiol and ERa17p on Early Gene expression in MDA-MB-231 cells

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A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer [RNA-seq]

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A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer [GRO-seq]

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A super enhancer-controlled BRD4/ERα-RET-ERα positive feedback loop promotes ERα-positive breast cancer [ChIP-seq]

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Regulation of TET2 gene expression and 5mC oxidation in breast cancer cells by estrogen signaling [hMeDIP-seq]

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