Mouse models for BRCA1 associated tumorigenesis: from fundamental insights to preclinical utility

Germline mutations in BRCA1 result in a significant predisposition for breast and ovarian cancer, with frequent LOH of the remaining wild type allele. Soon after the identification of BRCA1, several different knockout mice were generated to study its biological function in vivo. BRCA1, which is involved in DNA double-strand break (DSB) repair, appeared to be essential for embryonic proliferation and survival during mid-gestation. In contrast to human mutation carriers however, heterozygous mouse mutants did not show spontaneous cancer development. Therefore, a number of conditional mouse models were developed. while tumors of these mice show varying degrees of similarity with their human counterparts, two mouse models develop mammary tumors that lack expression of estrogen and progesterone receptors and ERBB2. This 'triple negative' signature is a characteristic feature of BRCA1-associated breast cancers, which can therefore not be treated with endocrine agents or ERBB2-targeting therapeutics. Promising drugs for treating BRCA1-mutated tumors include platinum compounds and PARP inhibitors, which are specifically toxic to DSB repair deficient cells. Although encouraging results have been reported, recent findings indicate that BRCA1/2 deficient ovarian tumors can escape from such targeted treatment by genetic reversion. This resistance mechanism might be studied in future mouse tumor models based on Brca1 truncating mutations mimicking defined human founder mutations.