| Two major breast cancer susceptibility genes have been identified and cloned. Mutations of BRCA1 and BRCA2 were found to account for more than half of all hereditary breast cancers in women, which makes up 5–10% of total breast cancers. Research studies have suggested that both genes are involved in monitoring cellular genome integrity, possibly in different yet dependent manners. Using a conditional mouse model, we have deleted Brca2 expression in the thymus or mammary glands of the mouse, to circumvent embryonic lethality seen in classical Brca2-deficient mice. In thymus-specific Brca2-deficient mice, we revealed that Brca2 is not required for the development of thymocytes. Brca2-mutant thymocytes undergo apoptosis in response to a number of DNA-damaging stress at a normal level. However, Brca2-mutant T cells activated by anti-CD3 and anti-CD28 antibodies acquired chromosomal aberrations and are prone to spontaneous apoptosis. In Brca2, p53 double mutant T cells, a dramatically higher level of genomic instability was observed but the cells did not exhibit a higher level of spontaneous death. Thymus-specific Brca2-mutants do not develop tumors, whereas Brca2, p53 double mutant mice develop mostly thymic lymphomas. In contrast, mammary gland-specific Brca2-mutant mice develop spontaneous mammary adenocarcinomas after a long latency. When one copy of the p53 gene is inactivated, the onset of adenocarcinomas development was shortened significantly compared to Brca2-mutant mice and a higher incidence rate compared to p53+/− mice. Nevertheless, mammary ductal and alveolar expansion during pregnancy, and apoptosis during involution, of Brca2 mutant mice appeared normal, suggesting that Brca2 is not required for normal mouse mammary gland development. |
