Co-regulated gene expression by estrogen receptor-a and liver receptor homolog-1 is a feature of the estrogen response in breast cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Koen Flach
PROVIDER: E-GEOD-49390 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Our findings establish a key role for LRH-1 in the regulation of ERa target genes in breast cancer cells and identify a mechanism in which co-operative binding of LRH-1 and ERa at estrogen response elements controls the expression of estrogen responsive g
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Project description:Estrogen receptor M-NM-1 (ERM-NM-1) is a nuclear receptor that is the driving transcription factor expressed in the majority of breast cancers. Recent studies have demonstrated that the liver receptor homolog-1 (LRH-1), another nuclear receptor, is ERM-NM-1-regulated in breast cancer cells. Further, LRH-1 stimulates proliferation and promotes motility and invasion of breast cancer cells. To determine the mechanisms of LRH-1 action in breast cancer cells, we carried out gene expression microarray analysis following siRNA-mediated LRH-1 knockdown. Interestingly, gene ontology (GO) category enrichment analysis of the genes differentially regulated in the presence or absence of LRH-1 identified estrogen responsive genes as the most highly enriched GO categories. To further define LRH-1 target genes, we performed chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) to identify genomic targets of LRH-1. Remarkably, ChIP-seq showed LRH-1 binding at many ERM-NM-1 binding sites. Analysis of select binding sites confirmed regulation of ERM-NM-1-regulated genes by LRH-1 through binding to estrogen response elements, as exemplified by the TFF1/pS2 gene. Finally, LRH-1 over-expression stimulated ERM-NM-1 recruitment, whilst LRH-1 knockdown reduced ERM-NM-1 recruitment to ERM-NM-1 binding sites. Taken together, our findings establish a key role for LRH-1 in the regulation of ERM-NM-1 target genes in breast cancer cells and identify a mechanism in which co-operative binding of LRH-1 and ERM-NM-1 at estrogen response elements controls the expression of estrogen-responsive genes. MCF-7 cells were transfected with LRH-1 siRNA #2, #3, or with a non-targeting siRNA (siControl) for 72 hours. Following assessment of RNA integrity, four biological replicates for each siRNA treatment were used for microarray analysis.
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Project description:Estrogen receptor α (ERα) is a nuclear receptor that is the driving transcription factor expressed in the majority of breast cancers. Recent studies have demonstrated that the liver receptor homolog-1 (LRH-1), another nuclear receptor, is ERα-regulated in breast cancer cells. Further, LRH-1 stimulates proliferation and promotes motility and invasion of breast cancer cells. To determine the mechanisms of LRH-1 action in breast cancer cells, we carried out gene expression microarray analysis following siRNA-mediated LRH-1 knockdown. Interestingly, gene ontology (GO) category enrichment analysis of the genes differentially regulated in the presence or absence of LRH-1 identified estrogen responsive genes as the most highly enriched GO categories. To further define LRH-1 target genes, we performed chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) to identify genomic targets of LRH-1. Remarkably, ChIP-seq showed LRH-1 binding at many ERα binding sites. Analysis of select binding sites confirmed regulation of ERα-regulated genes by LRH-1 through binding to estrogen response elements, as exemplified by the TFF1/pS2 gene. Finally, LRH-1 over-expression stimulated ERα recruitment, whilst LRH-1 knockdown reduced ERα recruitment to ERα binding sites. Taken together, our findings establish a key role for LRH-1 in the regulation of ERα target genes in breast cancer cells and identify a mechanism in which co-operative binding of LRH-1 and ERα at estrogen response elements controls the expression of estrogen-responsive genes.
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