Impact of ionizing radiation and genetic background on mammary tumorigenesis in p53-deficient mice

Loss of p53 function is known to compromise cell cycle regulation, inductio n of apoptosis, and DNA damage repair and can facilitate neoplastic transfo rmation of cells. Mutations in the p53 gene are identified frequently in br east carcinomas. Li-Fraumeni patients inheriting a mutant p53 allele have a n increased risk for developing tumors including breast cancer. Although mo use lines carrying mutations in the p53 gene have been generated, they die primarily of lymphoma and thus to date provide a limited model for the stud y of this disease and the role of p53 in nonfamilial breast cancer. An incr easing body of literature suggests that the incidence of various tumors is determined largely by the genetic background on which mutations are studied . In addition, population studies and studies in animals suggest that envir onmental factors, together with genetic factors, determine overall risk for development of specific types of tumors. We therefore examined the impact of genetic background together with exposure to ionizing radiation on the d evelopment of tumors, particularly mammary tumors, in p53-deficient animals . We report here that modifier alleles present in the BALB/c strain increas e the incidence of hemangiosarcomas [15 of 53 (28.3%); P=0.0007] in p53(-/- ) mice above rates reported previously in p53(-/-) mice on a mixed backgrou nd as compared to the incidence observed in DBA/p53(-/-) mice. However, no increase in the frequency of mammary tumors is seen in these mice or in p53 (-/-) DBA/2 animals, nor was an increase in mammary tumors observed in the DBA/2 p53(+/-) mice, even after exposure to 5 Gy of whole-body ionizing rad iation. In contrast, a significant increase in the incidence of mammary tum ors was observed in similarly treated BALB/c p53(+/-) mice (37.3% versus 6. 8%; P=0.0007). This was accompanied by a comparable decrease in the inciden ce of lymphomas. These results show that environmental agents together with genetic factors can increase the frequency and decrease the latency of mam mary tumors, leading to an incidence similar to that observed in Li-Fraumen i syndrome. Furthermore, it suggests that the risk of development of a part icular type of tumor by individuals deficient in p53 after exposure to dama ging agents can be influenced by modifier alleles.