TUMORIGENESIS AND A DNA-REPAIR DEFECT IN MICE WITH A TRUNCATING BRCA2MUTATION

Germline mutation of the BRCA2 gene carries a high risk of developing breast cancer. To study the function of this gene, we generated a muta tion in Brca2 in mice, Unlike other mutations in the Brca2 gene, which are lethal early in embryogenesis when homozygous, some of our homozy gous mutant mice survive to adulthood. These animals have a wide range of defects, including small size, improper differentiation of tissues , absence of germ cells and the development of lethal thymic lymphomas . Fibroblasts cultured from Brca2(-/-)embryos have a defect in prolife ration that may be mediated by over-expression of p53 and p21(Waf1/CIP 1). We show that BrcaZ is required for efficient DNA repair, and our r esults suggest that loss of the p53 checkpoint may be essential for tu mour progression triggered by mutations in BRCA2.