Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice

Cre-mediated deletion of exons 3 and 4 of the mouse Brca2 gene occurring specifically in mammary epithelial cells of conditional female mutants carrying a combination of loxP-modified and null Brca2 alleles resulted in a high incidence (77%) of breast tumors that were often palpable and developed in one or more glands after long latency (time for median tumor-free survival of approximately 1.4 years; total of 40 tumors in 20 animals). These invasive adenocarcinomas were histologically quite uniform, exhibiting predominantly a solid, nodular tumor pattern with very few variants, in striking contrast to the morphological heterogeneity of analogous Brca1-associated tumors. The karyotypes of tumor cells lacking Brca2 had various chromosomal aberrations and ranged from diploid to hypertetraploid, but this wide variability was incongruous with the histological appearance of carcinomas that was comparable between specimens. The implications of these observations in the context of models positing that Brca2 is involved in the maintenance of genomic stability are discussed.