KMT2C medaites the estrogen dependence of breast cancer through regulation of ERα enhancer function
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE100328 | GEO | 2018/06/30
REPOSITORIES: GEO
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Project description:The Estrogen Receptor alpha (ERα) controls key cellular functions in hormone responsive breast cancer by assembling in large functional multiprotein complexes. ERα ligands are classified as agonists and antagonist, according to the response they elicit, thus the molecular characterization of the of ERα nuclear iteractome composition following estrogen and antiestrogen stimulation whose is needed to understand their effects on estrogen target tissues, in particular breast cancer. To this aim interaction proteomics coupled to mass spectrometry (MS) was applied to map the ERα nuclear interacting partners in MCF7 breast cancer cell nuclei following estrogen and antiestrogen stimuli.
2020-09-02 | PXD018709 | Pride
Project description:Estrogen receptor alpha (ERα) is a ligand-activated nuclear receptor that directs proliferation and differentiation in selected cancer cell types including mammary-derived carcinomas. These master-regulatory functions of ERα require trans-acting elements such as the pioneer factor FOXA1 to establish a genomic landscape conducive to ERα control. Here, we identify the H3K4 methyltransferase KMT2C as necessary for hormone-driven ERα activity and breast cancer proliferation. KMT2C knockdown suppresses estrogen-dependent gene expression and causes H3K4me1 and H3K27ac loss selectively at ERα enhancers. Correspondingly, KMT2C loss impairs estrogen-driven breast cancer proliferation but has no effect on ER- breast cells. Whereas KMT2C loss disrupts estrogen-driven proliferation, it conversely promotes tumor outgrowth under hormone-depleted conditions. In accordance, KMT2C is one of the most frequently mutated genes in ER-positive breast cancer with KMT2C deletion correlating with significantly shorter progression-free survival on anti-estrogen therapy. From a therapeutic standpoint, KMT2C-depleted cells that develop hormone-independence retain their dependence on ERα, displaying ongoing sensitivity to ERα antagonists. We conclude that KMT2C is a key regulator of ERα activity whose loss uncouples breast cancer proliferation from hormone abundance.
| S-EPMC6107480 | biostudies-literature
Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186645 | GEO
Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186644 | GEO
Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186643 | GEO
Project description:ERα is essential for the anti-proliferative response of breast cancer cells not only to estrogen antagonists, but also to estrogen withdrawal by means of aromatase inhibitors. We explored here one of the simplest explanation for this, consisting in the possibility that ERα may have a wide genomic function in absence of ligands. The genomic binding of ERα in the complete absence of estrogen was then studied using hormone-dependent MCF7 cells, by chromatin immunoprecipitation sequencing. From these data, 4.2K highly significant binding events were identified, which were further confirmed by comparing binding events in cells expressing ERα to cells silenced for ERα. Apo-ERα binding sites were distributed close to genes with functions associated to cell growth and epithelial maintenance and show significant overlap with binding of other transcription factors important for luminal epithelial breast cancer. Interestingly, we found that upon ERα silencing cognate gene transcription in absence of estrogen is downregulated and this is accompanied by increased H27Kme3 at ERα binding sites. RNA-Seq experiments showed that unliganded ERα controls basal transcription widely, including both coding and noncoding transcripts. Genes affected by ERα silencing can be easily functionally related to mammary epithelium differentiation and maintenance, especially when considering downregulated genes. Additional functions related to inflammatory and immune response was observed. Our data unravel unexpected actions of ERα in breast cancer cells and provide a novel framework to understand success and failure of hormone therapy in breast cancer. Examination of unligandend estrogen receptor alpha (aERα) DNA interactions in control and aERα siRNA treated MCF7 cells.
2014-03-03 | E-GEOD-53532 | biostudies-arrayexpress
Project description:The Estrogen Receptor alpha (ERα), is a member of the nuclear receptor superfamily of trancriptional regulators that mediates estrogen signaling in hormone-responsive tumors controlling key cellular functions by assembling in large functional multiprotein complexes. Interaction proteomics coupled to mass spectrometry (MS) was applied to deeply characterize the nuclear interactors partners whom association with the receptor is mediated by RNAs
2019-07-29 | PXD012630 | Pride
Project description:Estrogen-receptor alpha (ERα)-dependent enhancers in the human breast cancer cell line MCF7 are a well-studied model system that allows high temporal resolution tracking of the different molecular events after hormone treatment and in which the enhancer and their target genes, as well as many of the molecular mechanisms operating in enhancer activation, are well defined. We use Capture-C to look at enhancer-promoter contact frequencies of GREB1 and NRIP1 genes across a time course (5, 30 and 60 min) after E2 addition to MCF7 cells which had been extensively starved of hormone. Additionally, ee look at the E2-dependent enhancer-promoter contact frequencies at these two loci in different contexts: in cells where the enhancer regions have been deleted; in cells treated with tamoxifen as well as with estradiol to assess the effect of different ERα ligands; and in cells pre-treated with the transcription inhibitors Flavopiridol and Triptolide to assess the role of active transcription.
2024-05-13 | GSE225617 | GEO
Project description:Estrogen Receptor alpha (ERα), a nuclear receptor with transcriptional activity, is a master regulator of estrogen signaling, widely known as therapeutic target in hormone-responsive breast cancer (BC). Moreover, ERα is highly expressed in approximately 80% of High Grade Serous Ovarian Cancer (HGSOC), the most common epithelial ovarian carcinoma. Despite some promising clinical trials evaluating endocrine therapy in this type of tumor, the role of ERα is still unknown. Epigenetic changes, such as DNA methylation, are emerging as key contributing factors to carcinogenesis. Disruptor of telomeric silencing-1-like (DOT1L), the only known histone methyl transferase capable to produce H3K79 mono, di and tri-methylation, modulates ERα actions in hormone-responsive BC. Considering this evidence, ERα-DOT1L association was confirmed in ERα-positive OC cells, PEO1 and PEO4, by Co-IP. DOT1L pharmacological inhibition by EPZ004777 (EPZ) revealed the involvement of this epigenetic enzyme in cell proliferation, cell cycle progression and apoptosis. Transcriptome profiling after ICI (a Selective Estrogen Receptor Degrader) and EPZ treatment, in both cell lines, has underlined a deep impact of both compounds on ERα-modulated genes, including the down-regulation of ERα itself. On the other hand, functional analysis showed that commonly affected transcripts are involved in different cellular processes, such as cancer cell survival, chemoresistance and cell cycle progression. Moreover, ChIP-qPCR performed on ERα promoter highlighted ERα and DOT1L co-localization, both in PEO1 and in PEO4 cells, which was reduced after EPZ treatment, suggesting a role of this complex on receptor transcriptional activity. In addition, drug combination studies performed with EPZ and ICI showed an additive effect in cell growth inhibition. Taken together, these results suggest DOT1L as a potential therapeutic target in the treatment of OC.
2019-11-04 | E-MTAB-8198 | biostudies-arrayexpress
Project description:The estrogen receptor-α (ERα) is a transcription factor which plays a critical role in controlling cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to induce or repress gene transcription. A deeper understanding of these transcriptional mechanisms may uncover novel therapeutic targets for ERα-dependent cancers. Here we show for the first time that BRD4 regulates ERα−induced gene expression by affecting elongation-associated phosphorylation of RNA Polymerase II (RNAPII P-Ser2) and histone H2B monoubiquitination (H2Bub1). Consistently, BRD4 activity is required for estrogen-induced proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide occupancy studies revealed an enrichment of BRD4 on transcriptional start sites as well as EREs enriched for H3K27ac and demonstrate a requirement for BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we further demonstrate that BRD4 occupancy correlates with active mRNA transcription and is required for the production of ERα-dependent enhancer RNAs (eRNAs). These results uncover BRD4 as a central regulator of ERα function and potential therapeutic target. ChIP-sequencing of BRD4, ERα and H2Bub1 in MCF7 cells treated with +/- estrogen treatment and or +/- JQ1 treatment in triplicates.
2014-07-10 | E-GEOD-55921 | biostudies-arrayexpress