Genome-wide activity of unliganded Estrogen Receptor-α in breast cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE53533 | GEO | 2014/03/02
SECONDARY ACCESSION(S): PRJNA232303
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-03-02 | E-GEOD-53533 | biostudies-arrayexpress
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.
| S-ECPF-GEOD-53532 | biostudies-other
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 that are independent of ligands. In the present work, we investigated the binding of ER? to chromatin in the absence of ligands and its functions on gene regulation. We demonstrated that in MCF7 breast cancer cells unliganded ER? binds to more than 4,000 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, compared with estrogen-induced binding. Moreover, we found that siRNA-mediated down-regulation of ER? in absence of estrogen is accompanied by changes in the expression levels of hundreds of coding and noncoding RNAs. Down-regulated mRNAs showed enrichment in genes related to epithelial cell growth and development. Stable ER? down-regulation 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, in the maintenance of the luminal-specific cistrome in breast cancer cells.
| S-EPMC3977241 | biostudies-literature
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: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: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
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:Genome-wide activity of unliganded Estrogen Receptor-α in breast cancer cells
| PRJNA232303 | ENA
Project description:Estrogen regulates several biological processes through estrogen receptor alpha (ERalpha) and ERbeta. ERalpha-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERalpha binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERalpha binding sites, respectively, with approximately 60% overlap. In both cell types, approximately 40% of estrogen-regulated genes associate with ERalpha binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor beta (TGF-beta), NF-kappaB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-beta treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERalpha DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERalpha binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERalpha-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERalpha-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.
| S-EPMC2593438 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-01-07 | E-GEOD-40767 | biostudies-arrayexpress