Women with germline mutations in BRCA1 are strongly predisposed to cancers of the ovary and fallopian tubes. Extensive epidemiological data have demonstrated a strong link between menstrual activity and risk of ovarian cancer in the general population. This led us to hypothesize that BRCA1 might predispose to ovarian cancer indirectly, by influencing ovarian granulosa cells, which play an important role in controlling menstrual cycle progression through their secretion of sex steroid hormones. Such hormones, as well as the peptide hormone mullerian inhibiting substance (MIS), also secreted by granulosa cells, can regulate ovarian epithelial tumor cell growth. We used the Cre-lox system to inactivate the mouse Brca1 gene in granulosa cells in order to test this hypothesis. A truncated form of the FSH receptor promoter, which directs expression exclusively in granulosa cells, was used as Cre driver. A majority (40/59) of Brca1 knockout mice had grossly visible cystic tumors either attached to the ovary, to the uterine horns, or with no demonstrable attachment to either of these organs. All tumors except one resembled human serous cystadenomas, which are benign tumors made up of the same cell type as ovarian serous carcinomas. A single tumor was histologically compatible with malignancy, although no sign of invasive or metastatic ability could be demonstrated. Strikingly, these tumors carried only the non-recombined (wild type) form of the floxed BRCA1 allele while the recombined (mutant) form was present only in granulosa cells in strong support of our hypothesis. Our proposal is focused on the elucidation of the mechanism of tumor predisposition in this experimental model, which we believe to be relevant to the strong tumor predisposition seen in women with germline BRCA1 mutations. We will identify the nature and tissue distribution of the ovarian and uterine cells affected by an absence of functional Brca1 in granulosa cells and will evaluate the reversibility of the phenotypic consequences of such defect and the protective role of pregnancy in Aim 1. We will characterize the consequences of such absence on the timing and hormonal activity of the various phases of the ovulatory cycle in Aim 2. The consequences of absence of a functional Brca1 on the spectrum of gene expression in ovarian granulosa cells will be examined in the last aim (Aim 3). Once the mechanisms of tumor predisposition are understood in this experimental model, we will be in a position to investigate its relevance to humans carrying a germline BRCA1 mutation and to use this knowledge to develop novel approaches to the clinical management of these individuals.
