Abstract 76: Liver receptor homologue-1 increases incidence of DMBA-induced mammary tumors
Authors: Kyren A. Lazarus, Kristy Brown, Morag Young, Jason Cain, Samantha Jayasekara, Rhiannon Coulson, Neil Watkins, Colin Clyne, Ashwini Chand
Journal: Cancer Research (2014)

Abstract Breast cancer is one of the most common malignancies globally. It accounts for approximately 15% of cancer-related deaths in Australian women. 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 tumour growth is not well understood. Therefore, we aimed to generate 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 was utilized with the LRH-1 transgenic mice to determine the role LRH-1 plays in promoting mammary carcinogenesis. Given clear in vitro roles for LRH-1 in breast cancer cell proliferation, we hypothesise LRH-1 stimulates mouse mammary epithelial cell proliferation and promotes DMBA-mediated mammary tumorigenesis. We demonstrate increase in proliferation markers Ki-67, PCNA and PH3 immunoreactivity in luminal epithelial cells of dox-treated animals indicating that LRH-1 plays a role in mammary cell proliferation in vivo. In DMBA treated animals, we observed a five-fold increase of dense pre-neoplastic epithelial foci (p=0.0267), and a four-fold increase in microscopic lesions in dox-treated animals (p=0.0003). 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 25.0% (out of twelve animals) in the dox treated cohort. LRH-1 is known synergise with β-catenin to induce cyclin D1/E1 mediated cell proliferation in vitro. We analysed transcript levels of cyclin D1/E1 and show a significant increase in dox treated animals with or without DMBA. Finally, we demonstrate an increase in the oncogene β-catenin nuclear localisation in the dox treated animals with or without DMBA. Taken together, these data suggest that LRH-1 increases incidence of DMBA-induced mammary tumours. Further analyses on mechanism(s) mediated by LRH-1 are warranted to fully understand its role in mammary tumorigenesis. Note: This abstract was not presented at the meeting. Citation Format: Kyren A. Lazarus, Kristy Brown, Morag Young, Jason Cain, Samantha Jayasekara, Rhiannon Coulson, Neil Watkins, Colin Clyne, Ashwini Chand. Liver receptor homologue-1 increases incidence of DMBA-induced mammary tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 76. doi:10.1158/1538-7445.AM2014-76