Genome-wide activity of unliganded Estrogen Receptor-α in breast cancer cells
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ABSTRACT:
PROVIDER: PRJNA232303 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1055980.fastq.gz | Fastqsanger.gz | |||
| SRR1055981.fastq.gz | Fastqsanger.gz | |||
| SRR1055982.fastq.gz | Fastqsanger.gz | |||
| SRR1055983.fastq.gz | Fastqsanger.gz | |||
| SRR1055984.fastq.gz | Fastqsanger.gz |
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Project description:Estrogen Receptor ? (ER?) has central role in hormone-dependent breast cancer and its ligand-induced functions have been extensively characterized. However, evidence exists that ER? has functions which are independent of ligands. In the present work, we investigated the binding of ER? to chromatin in absence of ligands, and its function(s) on gene regulation. We demonstrated that in MCF7 breast cancer cells unliganded ER? binds to more than four thousands chromatin sites. Unexpectedly, although almost entirely comprised in the larger group of estrogen-induced binding sites, we found that unliganded-ER? binding is specifically linked to genes with developmental functions, as compared to estrogen-induced binding. Moreover, we found that siRNA-mediated downregulation of ER? in absence of estrogen is accompanied by changes in the expression levels of hundreds of coding and noncoding RNAs. Downregulated mRNAs showed enrichment in genes related to epithelial cell growth and development. Stable ER? downregulation using shRNA, which caused cell-growth arrest, was accompanied by increased H3K27me3 at ER? binding sites. Finally, we found that FOXA1 and AP2? binding to several sites is decreased upon ER? silencing, suggesting that unliganded ER? participates, together with other factors, to the maintenance of the luminal-specific cistrome in breast cancer cells. Examination of unligandend estrogen receptor alpha (apoER?) DNA interactions in control and ER? siRNA treated MCF7 cells.
2014-03-03 | E-GEOD-53531 | biostudies-arrayexpress
Project description:Estrogen receptor alpha (ERa) has generally been thought to be transcriptionally inactive until it binds estrogen. Here we show that unliganded ERa, far from being transcriptionally inert, regulates a large number of genes both in vascular endothelial cells (ECs) and in mouse aorta. The genes regulated by unliganded ERa in the aorta (largely composed of smooth muscle cells) differ from those in ECs, and aorta- and EC-regulated promoters show enrichment in binding sites for distinct sets of transcription factors. In vitro, the presence of unliganded ERa decreases the migration and proliferation of ECs, and also increases proliferation of SMCs. Consistent with these effects on individual cells in vitro, mice lacking ERa, in the absence of estrogen, show significantly less SMC proliferation and medial thickening after carotid artery wire injury than ER intact mice. The effects of unliganded ERa on vascular gene expression, cell function in vitro and vascular injury responses in vivo are all reversed by the addition of estrogen. Taken together, these results indicate that unliganded ERa regulates vascular gene expression, vascular cell function, and vascular injury responses, and that the cardiovascular protective effects of estrogen may largely be due to the reversal of these effects of unliganded ERa. These results have important implications for the vascular health of men and post-menopausal women with vascular ERa and low circulating levels of estrogen. This study also raises the possibility that the steroid receptor family could have substantial hormone-independent functions in the vasculature and in other tissues.
2016-11-22 | GSE51535 | GEO
Project description:Estrogen Receptor α (ERα) has central role in hormone-dependent breast cancer and its ligand-induced functions have been extensively characterized. However, evidence exists that ERα has functions which are independent of ligands. In the present work, we investigated the binding of ERα to chromatin in absence of ligands, and its function(s) on gene regulation. We demonstrated that in MCF7 breast cancer cells unliganded ERα binds to more than four thousands chromatin sites. Unexpectedly, although almost entirely comprised in the larger group of estrogen-induced binding sites, we found that unliganded-ERα binding is specifically linked to genes with developmental functions, as compared to estrogen-induced binding. Moreover, we found that siRNA-mediated downregulation of ERα in absence of estrogen is accompanied by changes in the expression levels of hundreds of coding and noncoding RNAs. Downregulated mRNAs showed enrichment in genes related to epithelial cell growth and development. Stable ERα downregulation using shRNA, which caused cell-growth arrest, was accompanied by increased H3K27me3 at ERα binding sites. Finally, we found that FOXA1 and AP2γ binding to several sites is decreased upon ERα silencing, suggesting that unliganded ERα participates, together with other factors, to the maintenance of the luminal-specific cistrome in breast cancer cells.
2014-03-03 | GSE53531 | 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:Estrogen Receptor subtypes (ERα and ERβ) are transcription factors sharing similar structure, however, they often perform opposite roles in breast cancer’s cell proliferation and tumor progression. Besides the well-characterized genomic actions of ERs upon ligand binding, rapid non-genomic cytoplasmic changes together with the recently discovered ligand-free action of ERs are emerging as key regulators of tumorigenesis. The identification of cytoplasmic interaction partners of unliganded ERα and ERβ may help characterize the molecular basis of the extra-nuclear mechanism of action of these receptors, revealing novel mechanisms to explain their role in breast cancer response or resistance to endocrine therapy. To this aim, in this study, cytoplasmic extracts from stably expressing TAP-ERα and -ERβ MCF-7 cell clones were subjected to interaction proteomics in the absence of estrogen stimulation, leading to the identification of 84 and 142 proteins associated with unliganded ERα and ERβ, respectively. Functional analyses of ER subtype-specific interactomes revealed significant differences in the molecular pathways associated to each receptor in the cytoplasm. This work reports the first identification of the unliganded ERα and ERβ cytoplasmic interactomes in breast cancer cells, providing novel experimental evidence on the non-genomic effects of ERs in the absence of hormonal stimulus.
2015-03-11 | PXD001202 | Pride
Project description:The Estrogen Receptor beta (ERβ), is a member of the nuclear receptor superfamily of trancriptional regulators, with oncosuppressive activities, antagonizing hormone-induced carcinogenesis and inhibiting growth and oncogenic functions in breast cancers (BCs). It is able to exert specific biological functions also in the absence of estrogen stimuli. Interaction proteomics coupled to mass spectrometry (MS) was applied to deeply characterize the nuclear interactors cooperating with unliganded ERβ and the role of RNA in mediating these iteractions.
2017-12-19 | PXD006720 | Pride
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.
2014-03-03 | GSE53532 | GEO
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Project description:Retinoic acid receptor-alpha (RAR alpha) is a known estrogen target gene in breast cancer cells. The consequence of RAR alpha induction by estrogen was previously unknown. We now show that RAR alpha is required for efficient estrogen receptor-alpha (ER)-mediated transcription and cell proliferation. RAR alpha can interact with ER-binding sites, but this occurs in an ER-dependent manner, providing a novel role for RAR alpha that is independent of its classic role. We show, on a genome-wide scale, that RAR alpha and ER can co-occupy regulatory regions together within the chromatin. This transcriptionally active co-occupancy and dependency occurs when exposed to the predominant breast cancer hormone, estrogen--an interaction that is promoted by the estrogen-ER induction of RAR alpha. These findings implicate RAR alpha as an essential component of the ER complex, potentially by maintaining ER-cofactor interactions, and suggest that different nuclear receptors can cooperate for effective transcriptional activity in breast cancer cells. RAR alpha silenced breast cancer MCF-7 cell lines or control siRNA in the presence of estrogen or a vehicle. MCF-7 cells were hormone-depleted for 3 d and treated with 100 nM estrogen for 12 h. There were three biological replicates for each of the four different groups.
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