Department of Surgery & Cancer, Imperial College London
Doi
Abstract
Estrogens play a critical role in the development and progression of breast cancer. The biological functions of estrogen are mainly mediated by estrogen receptors (ER), which act by regulating gene expression in breast cancer cells. Previously our laboratory identified liver receptor homologue-1 (LRH-1), a member of the nuclear receptor superfamily of transcription factors to which ER also belongs, as an estrogen-responsive gene. Subsequent work showed that LRH-1 is important in mediating the growth of breast cancer cells. Herein, I show that LRH-1 in turn regulates the expression of ERα, providing a positive feedback loop, which may act to promote stable co-expression of ERα and LRH-1 in breast cancer cells. To better define the mechanisms of LRH-1 action in breast cancer cells, gene expression microarray analysis was performed following RNA interference mediated LRH-1 knockdown. Microarray analysis demonstrated that LRH-1 regulates the expression of many estrogen-responsive genes. ChIP-seq analysis, carried out to identify global LRH-1 binding sites, showed that LRH-1 is recruited to a substantial proportion of estrogen-regulated genes, frequently binding to ERα binding sites, suggesting LRH-1 directly regulates a subset of ERα-target genes in breast cancer cells. Analysis of select binding sites confirmed the direct LRH-1 regulation of ERα target genes through LRH-1 binding to estrogen response elements (ERE), as exemplified by the TFF1/pS2 gene. Moreover, LRH-1 was shown to stimulate the recruitment of ERα to the ERE in the shared/common target genes, suggesting a co-operative function between LRH-1 and ERα. Collectively, these findings show that LRH-1 is a key mediator of the estrogen response in breast cancer cells and raises the possibility of targeting LRH-1 for the treatment of breast cancer. Towards this end, I also describe the identification of novel LRH-1 antagonists that inhibit breast cancer cell growth. Development of these compounds will offer investigational tools for validating the importance of LRH-1 in breast cancer, towards a therapeutic strategy in breast cancer treatment.Open Acces
