Conditional overexpression of liver receptor homolog-1 in female mouse mammary epithelium results in altered mammary morphogenesis via the induction of tgf-ß Academic Article uri icon


MeSH Major

  • Breast Neoplasms
  • Mammary Glands, Animal
  • Morphogenesis
  • Receptors, Cytoplasmic and Nuclear
  • Transforming Growth Factor beta
  • Up-Regulation


  • 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-β 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-β 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-β expression. The regulation of TGF-β 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-β expression and downstream signaling in mouse mammary glands.

publication date

  • January 2014



  • Academic Article



  • eng

Digital Object Identifier (DOI)

  • 10.1210/en.2013-1948

PubMed ID

  • 24564400

Additional Document Info

start page

  • 1606

end page

  • 17


  • 155


  • 5