Abstract
Oestrogen 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, 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 ERα binding sites. Analysis of select binding sites confirmed regulation of ERα−regulated genes by LRH-1 through binding to oestrogen response elements, as exemplified by the TFF1/pS2 gene. Finally, LRH-1 overexpression stimulated ERα recruitment, while 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 oestrogen response elements controls the expression of oestrogen-responsive genes.
Highlights
Oestrogens play diverse roles in the body, most notably in the development and maintenance of female and male reproductive systems and secondary sexual characteristics [1]
To determine if liver receptor homolog-1 (LRH-1) directly regulates the expression of oestrogen-responsive genes, Chromatin immunoprecipitation (ChIP)-seq in MCF-7 cells was carried out using antibodies for LRH-1
The bile acid receptor FXR is implicated in crosstalk with LRH-1 and ChIP-seq for FXR and LRH-1 reveals that almost a quarter of hepatic LRH-1 binding sites are located in close proximity to FXR binding sites, suggesting that co-operativity between LRH-1 and FXR is important for the regulation of metabolic genes in the liver [78,79]
Summary
Oestrogens play diverse roles in the body, most notably in the development and maintenance of female and male reproductive systems and secondary sexual characteristics [1]. Oestrogens play a central role in promoting breast cancer growth [4], as well as being implicated in uterine and ovarian cancers [5,6]. ERa activity is inhibited in breast cancer patients with endocrine therapies using anti-oestrogens, such as tamoxifen and fulvestrant or by inhibiting oestrogen biosynthesis either by using aromatase inhibitors in postmenopausal women or with lutenising hormone releasing hormone (LHRH) agonists in premenopausal women. These therapies are well-tolerated and have been a major factor in the improvement in patient survival seen in recent years. A better understanding of the mechanisms of ERa action would aid patient stratification and identify new therapeutic targets
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