A Quest for Better Mouse Models of Breast and Ovarian Cancers

Inheritedmutations in the BRCA1 (breast cancer 1, early onset) gene increase the risk of female breast and ovarian cancers. About 65% and 40% of females who inherit BRCA1 mutations will develop breast and ovarian cancer, respectively (Antoniou et al., 2003). To address specific roles of BRCA1 in the normal development and cancer pathogenesis, a number of genetically modified mouse models have been developed. It has been shown that mammary epithelium-specific inactivation of Brca1 alone is insufficient for cancer induction. However, mammary carcinomas can be induced by concurrent inactivation of Brca1 together with p53 (aka TP53/Trp53) gene, another tumor suppressor gene commonly inactivated in familial breast carcinomas. Similar to human breast cancers mutant for BRCA1, mouse BRCA1/P53 deficient tumors are mainly basaloid and triple-negative (no expression of estrogen receptor, progesterone receptor and HER/ERBB2 protein) (Liu et al., 2007). Transplantation of the ovarian surface epithelium (OSE) cells null for Brca1 and p53 genes resulted in the formation of carcinomas, which closely resembled high-grade serous ovarian carcinomas (HGSOC), the most common type of ovarian carcinoma (Orsulic et al., 2002). Albeit highly valuable, the models used in those studies were focused on genetic modification in target cells and did not allow for direct testing of the role of non-autonomous factors in the pathogenesis of cancers associated with BRCA1 deficiency. To address this problem, Liu et al., 2015 developed newmousemodels allowing Cre-loxPmediated gene modifications in tissues expressing the Müllerian inhibiting substance receptor type 2 (Mis2r, aka anti-Müllerian hormone receptor type 2) and follicle stimulating hormone receptor (Fshr). The authors established patterns of expression directed by the Mis2r and truncated Fshrpromoters, and inactivatedfloxed Brca1 and p53 via Cre recombinase driven by these promoters. Consistent with the detected expression of Mis2r and Fshr transgenes in the mammary gland, the authors observed the formation of Brca1 and p53 deficient tumors featuring preferentially