Conditional overexpression of liver receptor homolog-1 in female mouse mammary epithelium results in altered mammary morphogenesis via the induction of TGF-beta

Kyren Lazarus, Kristy A Brown, Morag J Young, Zhe Zhao, Rhiannon Coulson, Ashwini L Chand, Colin Clyne

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

Liver Receptor Homolog-1 (LRH-1) is an orphan nuclear receptor that belongs to the NR5A subgroup of nuclear receptors. LRH-1 induces key genes to regulate metabolic process, ovarian function, cancer cell proliferation and steroidogenesis. In the breast, LRH-1 modulates and synergizes with endogenous estrogen signalling to promote breast cancer cell proliferation. We used siRNA knockdown strategies in order to deplete LRH-1 in breast cancer cells and followed with microarray analysis to identify LRH-1 dependent mechanisms. We identified key genes involved in TGF-beta signalling to be highly responsive to LRH-1 knockdown. This relationship was validated in two breast cancer cell lines over-expressing LRH-1 in vitro and in a novel transgenic mouse with targeted LRH-1 over-expression in mammary epithelial cells. Notably, TGF-beta signalling was activated in LRH-1 over expressing breast cancer cells and mouse mammary glands. Further analyses of mammary gross morphology revealed a significant reduction in mammary lateral budding after LRH-1 over expression. These findings suggest that the altered mammary morphogenesis in LRH-1 transgenic animals is mediated via enhanced TGF-beta expression. The regulation of TGF-beta isoforms and SMAD2/3-mediated downstream signalling by LRH-1 also implicates a potential contribution of LRH-1 in breast cancer. Collectively this data demonstrates that LRH-1 regulates TGF-beta expression and downstream signalling in mouse mammary glands.
Original languageEnglish
Pages (from-to)1606 - 1617
Number of pages12
JournalEndocrinology
Volume155
Issue number5
DOIs
Publication statusPublished - 2014

Cite this