Mechanism of Ovarian Epithelial Tumor Predisposition in Individuals Carrying Germline BRCA1 Mutations

摘要

Women with germline mutations in BRCA1 are strongly predisposed to cancers of the ovary and fallopian tubes. Given the strong link between menstrual activity and risk of ovarian cancer in the general population, we hypothesized that BRCA1 might predispose to ovarian cancer indirectly, by influencing ovarian granulosa cells, which play an important role in controlling menstrual cycle progression. We used the Cre-lox system to inactivate the mouse Brca1 gene in granulosa cells. A truncated form of the FSH receptor promoter was used as Cre driver. Our most recent results show that a majority (40 of 59) of mutant mice develop grossly visible cystic tumors either attached to the ovary or the uterine horns. These tumors resembled human serous cyst adenomas, which are benign tumors made up of the same cell type as ovarian serous carcinomas. We confirmed that these tumors carried only the wild type allele of the floxed Brca1 allele while the mutant form was present in granulosa cells. These findings strongly support our initial hypothesis that Brca1 influences tumor development cell non-autonomously, through an effector secreted by granulosa cells. We developed tools such as long-term cultures of human granulosa cells, which will be used to compare the gene expression patterns of wild type and mutant granulosa cells in the second year. We also obtained preliminary data suggesting that the dynamics of the hormonal changes associated with the estrous cycle are slightly different in mutant mice, suggesting that the influence of granulosa cells on tumor predisposition in this animal model may be mediated through their role in the ovulatory cycle. Finally, we show evidence that the mutant mice show increased proliferative activity in epithelial cells lining the uterus and endometrium and endometrial glands, strongly supporting our view that ovarian epithelial tumors are derived from components of the mullerian tract.