Abstract
BackgroundLiver Receptor Homolog 1 (LRH-1, NR5A2) is an orphan nuclear receptor that is over-expressed in cancers in tissues such as the breast, colon and pancreas. LRH-1 plays important roles in embryonic development, steroidogenesis and cholesterol homeostasis. In tumor cells, LRH-1 induces proliferation and cell cycle progression. High LRH-1 expression is demonstrated in breast cancers, positively correlating with ERα status and aromatase activity. LRH-1 dependent cellular mechanisms in breast cancer epithelial cells are poorly defined. Hence in the present study we investigated the actions of LRH-1 in estrogen receptor α (ERα) positive breast cancer cells.ResultsThe study aimed to investigate LRH-1 dependent mechanisms that promote breast cancer proliferation. We identified that LRH-1 regulated the expression of Growth Regulation by Estrogen in Breast Cancer 1 (GREB1) in MCF-7 and MDA-MB-231 cells. Over-expression of LRH-1 increased GREB1 mRNA levels while knockdown of LRH-1 reduced its expression. GREB1 is a well characterised ERα target gene, with three estrogen response elements (ERE) located on its promoter. Chromatin immunoprecipitation studies provided evidence of the co-localisation of LRH-1 and ERα at all three EREs. With electrophoretic mobility shift assays, we demonstrated direct binding of LRH-1 to EREs located on GREB1 and Trefoil Factor 1 (TFF1, pS2) promoters. LRH-1 and ERα co-operatively activated transcription of ERE luciferase reporter constructs suggesting an overlap in regulation of target genes in breast cancer cells. Over-expression of LRH-1 resulted in an increase in cell proliferation. This effect was more pronounced with estradiol treatment. In the presence of ICI 182,780, an ERα antagonist, LRH-1 still induced proliferation.ConclusionsWe conclude that in ER-positive breast cancer cells, LRH-1 promotes cell proliferation by enhancing ERα mediated transcription of target genes such as GREB-1. Collectively these findings indicate the importance of LRH-1 in the progression of hormone-dependent breast cancer and implicate LRH-1 as a potential avenue for drug development.
Highlights
Exposure of breast tissue to circulating hormones is a key risk factor in breast cancer incidence [1,2,3]
LRH-1 bound directly to estrogen response elements (ERE) sequences present on the promoters of two well characterised, estrogen responsive genes GREB1 and Trefoil Factor 1 (TFF2 or pS2). These findings indicate that LRH-1 acts synergistically with estrogen receptor a (ERa) to induce transcription of GREB1 and unravels a new mechanism of action for LRH-1 in inducing cancer cell proliferation
Having confirmed over- and under- expression of LRH-1 in MCF-7 cells, we measured expression of GREB1, a gene previously identified in microarray data sets as significantly regulated by LRH-1
Summary
Exposure of breast tissue to circulating hormones is a key risk factor in breast cancer incidence [1,2,3]. In this report we analysed the effect of the orphan nuclear receptor NR5A2 ( termed Liver Receptor Homolog-1, LRH-1) on the transcriptional regulation of Growth Regulation by Estrogen in Breast Cancer (GREB1) and breast cancer proliferation. LRH-1 has well established roles in metabolic pathways involved in bile acid synthesis [5,6] and reverse cholesterol transport [7,8]. It is highly expressed in the ovary where it is vital for the regulation of steroidogenesis [9,10]. Liver Receptor Homolog 1 (LRH-1, NR5A2) is an orphan nuclear receptor that is over-expressed in cancers in tissues such as the breast, colon and pancreas. In the present study we investigated the actions of LRH-1 in estrogen receptor a (ERa) positive breast cancer cells
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