期刊
NUCLEIC ACIDS RESEARCH
卷 41, 期 22, 页码 10228-10240出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt827
关键词
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资金
- Cancer Research UK [C37/A12011, C37/A9335]
- Breast Cancer Campaign [2007MayPR17]
- Cancer Research UK China
- Medical Research Council
- Dutch Cancer Society KWF
- Netherlands Organisation for Scientific Research NWO Veni grant
- Imperial College London
- Cancer Research UK [12011] Funding Source: researchfish
- Medical Research Council [1107693] Funding Source: researchfish
Oestrogen receptor alpha (ER alpha) 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, regulates breast cancer cell proliferation and promotes motility and invasion. To determine the mechanisms of LRH-1 action in breast cancer, we performed gene expression microarray analysis following RNA interference for LRH-1. Interestingly, gene ontology (GO) category enrichment analysis of LRH-1-regulated genes identified oestrogen-responsive genes as the most highly enriched GO categories. Remarkably, chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) to identify genomic targets of LRH-1 showed LRH-1 binding at many ER alpha binding sites. Analysis of select binding sites confirmed regulation of ER alpha-regulated genes by LRH-1 through binding to oestrogen response elements, as exemplified by the TFF1/pS2 gene. Finally, LRH-1 overexpression stimulated ER alpha recruitment, while LRH-1 knockdown reduced ER alpha recruitment to ER alpha binding sites. Taken together, our findings establish a key role for LRH-1 in the regulation of ER alpha target genes in breast cancer cells and identify a mechanism in which co-operative binding of LRH-1 and ER alpha at oestrogen response elements controls the expression of oestrogen-responsive genes.
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