Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice - A model for Li-Fraumeni syndrome

Breast cancer is the most frequent tumor type among women in the United Sta tes and in individuals with Li-Fraumeni syndrome. The p53 tumor suppressor gene is altered in a large proportion of both spontaneous breast malignanci es and Li-Fraumeni breast cancers. This suggests that loss of p53 can accel erate breast tumorigenesis, yet p53-deficient mice rarely develop mammary t umors. To evaluate the effect of p53 loss on mammary tumor formation, the p 53(null) allele was back-crossed onto the BALB/c genetic background. Median survival was 15.4 weeks for BALB/c-p53(-/-) mice compared to 54 weeks for BALB/c-p53(+/-) mice. Sarcomas and lymphomas were the most frequent tumor t ypes in BALB/c-p53(-/-) mice, whereas 55% of the female BALB/c-p53(+/-) mic e developed mammary carcinomas. The mammary tumors were highly aneuploid, f requently lost the remaining wild-type p53 allele, but rarely lost BRCA1. A lthough mammary tumors were rarely detected in BALB/c-p53(-/-) female mice, when glands from BALB/ c-p53(-/-) mice were transplanted into wild-type BA LB/c hosts, 75% developed mammary tumors. The high rate of mammary tumor de velopment in the BALB/c background, but not C57Bl/6 or 129/Sv, suggests a g enetic predisposition toward mammary tumorigenesis. Therefore, the BALB/c-p 53(+/-) mice provide a unique model for the study of breast cancer in Li-Fr aumeni syndrome. These results demonstrate the critical role that the p53 t umor suppressor gene plays in preventing tumorigenesis in the mammary gland .