Journal
ENDOCRINOLOGY
Volume 155, Issue 5, Pages 1606-1617Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2013-1948
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Funding
- National Health and Medical Research Council of Australia (NHMRC) [1027707]
- Swinburne University Postgraduate Award
- NHMRC Career Development Award [GNT1007714]
- US Department of Defense Breast Cancer Research Program [W81XWH-10-1-0913]
- Victorian Government's Operational Infrastructure Support Program
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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 signaling to promote breast cancer cell proliferation. We used small interfering RNA knockdown strategies 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 signaling to be highly responsive to LRH-1 knockdown. This relationship was validated in 2 breast cancer cell lines overexpressing LRH-1 in vitro and in a novel transgenic mouse with targeted LRH-1 overexpression in mammary epithelial cells. Notably, TGF-beta signaling was activated in LRH-1-overexpressing breast cancer cells and mouse mammary glands. Further analyses of mammary gross morphology revealed a significant reduction in mammary lateral budding after LRH-1 overexpression. 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 signaling by LRH-1 also implicates a potential contribution of LRH-1 in breast cancer. Collectively, these data demonstrate that LRH-1 regulates TGF-beta expression and downstream signaling in mouse mammary glands.
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