A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State

• Mouse model reproducing both, cell-autonomous and cell-nonautonomous mechanisms of cancer risk in BRCA1 mutation carriers.
• The Müllerian and mesonephric ducts are embryologically linked, possibly accounting for Müllerian clear cell carcinomas.
• Foci of endosalpingiosis are at increased risk of cancer in the absence of a functional Brca1.Most individuals with familial predisposition to breast and ovarian cancer carry germline mutations in BRCA1. Cancer predisposition in such carriers is due not only to effects of these mutations in tissues with an elevated cancer risk, but also in organs that control the menstrual cycle, which influences such tissues. The animal model that we developed mimics both mechanisms, which will facilitate our understanding of the contribution of menstrual cycle regulation to risk of these cancers. Our characterization of this model also led to insights into the origin of the serous and clear cell subtypes of ovarian cancer.

ABSTRACTPredisposition to breast and extrauterine Müllerian carcinomas in BRCA1 mutation carriers is due to a combination of cell-autonomous consequences of BRCA1 inactivation on cell cycle homeostasis superimposed on cell-nonautonomous hormonal factors magnified by the effects of BRCA1 mutations on hormonal changes associated with the menstrual cycle. We used the Müllerian inhibiting substance type 2 receptor (Mis2r) promoter and a truncated form of the Follicle stimulating hormone receptor (Fshr) promoter to introduce conditional knockouts of Brca1 and p53 not only in mouse mammary and Müllerian epithelia, but also in organs that control the estrous cycle. Sixty percent of the double mutant mice developed invasive Müllerian and mammary carcinomas. Mice carrying heterozygous mutations in Brca1 and p53 also developed invasive tumors, albeit at a lesser (30%) rate, in which the wild type alleles were no longer present due to loss of heterozygosity. While mice carrying heterozygous mutations in both genes developed mammary tumors, none of the mice carrying only a heterozygous p53 mutation developed such tumors (P < 0.0001), attesting to a role for Brca1 mutations in tumor development. This mouse model is attractive to investigate cell-nonautonomous mechanisms associated with cancer predisposition in BRCA1 mutation carriers and to investigate the merit of chemo-preventive drugs targeting such mechanisms.