BRCA1 conditional knockouts. BRCA1 LoxP mutations allow selective inactivation of the gene in mammary epithelial cells (accelerating breast tumor formation) and in cardiomyocytes (impairing cardiac remodeling that may increase the risk of heart failure following myocardial infarction).
Although germ-line mutations of BRCA1 increase susceptibility to familial breast and ovarian cancer, embryonic lethality of BRCA1 null mutations in mice precluded study of the role of BRCA1 in mammary gland development and neoplasia. To make it possible to study BRCA1 function in different tissues at different stages of development, conditional mutants in exon11 of the BRCA1 gene were constructed using the Cre-Lox approach. Cre-mediated excision of exon 11 of Brca1 in mouse mammary epithelial cells caused increased apoptosis, abnormal ductal development, and mammary tumor formation after a long latency.1 The formation of mammary tumors was accelerated in female mice in which Brca1 had been selectively inactivated in mammary epithelial cells when an inactive p53 gene also was introduced. Cre-mediated excision of floxed BRCA1 in mouse cardiomyocytes impairs cardiac remodeling, leading to poor ventricular function and higher mortality in response to ischaemic or genotoxic stress, suggesting that BRCA1 mutations in humans may increase the risk of cardiac failure2.