Potential Beneficial Effects Of The Brca1 Mutation Carrier State On Bone Strength

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL We previously suggested, based on observations in a mouse model in which we conditionally inactivated Brca1 in ovarian granulosa cells, that mutant mice are exposed to higher estradiol levels and also have prolonged estradiol exposure unopposed by progesterone due to an increase in the proestrus phase of their estrus cycle relative to metestrus. We sought to examine the biological significance of increased hormonal stimulation in homozygous Brca1 conditional knockout mice and to test the hypothesis that the effect is also present in mice with a heterozygous mutation such as present in human BRCA1 mutation carriers. We use endometrial cellular proliferation as an indicator for short-term effects of a Brca1mutation. Long-term effects were examined by measurements of long bone parameters using micro-computed tomography. The relative effects of heterozygous versus homozygous Brca1 mutations were evaluated by measuring the expression of enzymes involved in estradiol biosynthesis in granulosa cells. Mutant mice synchronized in the proestrus phase of their estrus cycle showed an increase in endometrial stromal cell proliferation in (P = .01). Mutant mice also showed an increase in trabecular bone density (P = .01) and femoral length (P = .02). Protein expression of aromatase and Hsd3B was higher in granulosa cells of mice carrying a heterozygous mutation in their ovarian granulosa cells compared to wild type littermates (P = .005 and .006 respectively). Our results provide a potential explanation for epidemiological observations to the effect that height is associated with increased risk for breast and ovarian cancer. The results also suggest that BRCA1 mutations, while associated with increased cancer risk, may also have some inherent advantages such as increased bone strength that may have contributed to the maintenance of mutated BRCA1 alleles in the human gene pool. Heterozygous Brca1 mutations such as present in human BRCA1 mutation carriers are not silent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3279. doi:1538-7445.AM2012-3279