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Impact of Ionizing Radiation and Genetic Background on Mammary Tumorigenesis in p53-deficient Mice¹

Curriculum in Genetics and Molecular Biology [M. G. B.], Division of Laboratory Animal Medicine [S. L. T.], and Departments of Medicine [D. C. B., V. L. C., B. H. K.] and Pathology [V. G.], University of North Carolina, Chapel Hill, North Carolina 27599

Loss of p53 function is known to compromise cell cycle regulation, inductionof apoptosis, and DNA damage repair and can facilitate neoplastic transformation of cells. Mutations in the p53 gene are identified frequently in breast carcinomas. Li-Fraumeni patients inheriting a mutant p53 allele have an increased risk for developing tumors including breast cancer. Although mouse 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 study of this disease and the role of p53 in nonfamilial breast cancer. An increasing 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 environmental 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 development of tumors, particularly mammary tumors, in p53-deficient animals. We report here that modifier alleles present in the BALB/c strain increase 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 background 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 radiation. In contrast, a significant increase in the incidence of mammary tumors 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 incidence of lymphomas. These results show that environmental agents together with genetic factors can increase the frequency and decrease the latency of mammary tumors, leading to an incidence similar to that observed in Li-Fraumeni syndrome. Furthermore, it suggests that the risk of development of a particular type of tumor by individuals deficient in p53 after exposure to damaging agents can be influenced by modifier alleles.

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