Potential Consequences of the Brca1 Mutation Carrier State on Estrogen Responsive Organs

Incessant menstrual cycle activity, uninterrupted by either pregnancy or oral contraceptive use, is the most important risk factor for sporadic ovarian cancer. Menstrual cycle progression is partly controlled by steroid hormones such as estrogens and others that are secreted by ovarian granulosa cells. We showed earlier that mice carrying a homozygous granulosa cell specific knock out of Brca1, the homolog of BRCA1that is associated with familial ovarian cancer predisposition in humans, develop benign epithelial tumors in their reproductive tract. These tumors are driven, at least in part, by a prolongation of the proestrus phase of the estrus cycle (equivalent to the follicular phase of the menstrual cycle) in Brca1 mutant mice, resulting in prolonged unopposed estrogen stimulation. Mutant mice synchronized in proestrus also showed increased circulating estradiol levels, but the possibility that this changealso plays a role in tumor predisposition was not investigated. We sought to determine whether these changes in hormonal stimulation result in measurable changes in tissues targeted by estrogen outside the ovary. Here we show that mice carrying a Brca1 mutation in ovarian granulosa cells show increased endometrial proliferation during proestrus, implying that the effects of Brca1 inactivation on estrogen stimulation have short-term consequences, at least on this target organ. We further show that mutant mice develop increased femoral trabecular thickness and femoral length, which are well-known consequences of chronic estrogen stimulation. Estrogen biosynthesis by granulosa cells was increased not only in Users may view, print, copy, download and text and datamine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Corresponding author: Louis Dubeau, Ezralow Tower room 6338, USCNorris, Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033; [email protected]; tel: 323-865-0720; fax: 323-865-0077. Conflict of interest: none declared. HHS Public Access Author manuscript Lab Invest. Author manuscript; available in PMC 2015 August 10. Published in final edited form as: Lab Invest. 2012 June ; 92(6): 802–811. doi:10.1038/labinvest.2012.58. A uhor M anscript