Breast cancer is one of the most common malignancies globally and it accounts for approximately 15% of cancer-related deaths in Australian women. Nuclear receptors play a prominent role in breast tumorigenesis. The orphan nuclear receptor liver receptor homolog-1 (LRH-1) promotes increased cell proliferation, motility and invasion in breast cancer cell lines. Additionally, high LRH-1 expression in human breast cancers is positively associated with estrogen receptor alpha status and aromatase activity. However, the role of LRH-1 in vivo is not well understood. Therefore, we generated a doxycycline (dox)-inducible mammary epithelial specific LRH-1 knock-in mouse in order to define the role of LRH-1 in mammary epithelial proliferation in vivo. In addition, the Dimethylbenz(a)anthracene (DMBA) induced mammary tumour model along with the LRH-1 transgenic mice were utilized to determine the role LRH-1 plays in promoting mammary carcinogenesis.

We show an increase in Ki-67 immunoreactivity in luminal epithelial cells of dox-treated animals. Additionally, we demonstrated an increase in Cyclin D1/E1 mRNA in dox treated mammary epithelial cells. This data indicates that LRH-1 plays a role in mammary cell proliferation in vivo. We also demonstrated that LRH-1 over-expression significantly reduced breast tumour-free survival in the transgenic DMBA model (no dox n=11; dox n=12, Mantel-Cox test p=0.0375). Tumour penetrance in DMBA animals not treated with dox was 9% (out of eleven animals) versus 41.7% (out of twelve animals) in the dox treated cohort.  Further, whole mount analysis revealed a five-fold increase of dense pre-neoplastic epithelial foci in dox treated animals (p=0.0267). Taken together, these data suggest that LRH-1 accelerates DMBA-induced mammary tumours. Therefore, further analyses on mechanism(s) mediated by LRH-1 are warranted to fully understand its role in breast tumorigenesis.