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Mammary Tumor Formation in p53- and BRCA1-deficient Mice¹

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

The inheritance of a mutant copy of the BRCA1 gene greatly increases a woman’s lifetime risk for ovarian and breast cancer. While a homologous gene has been identified in mouse, mice carrying mutations in this gene do not display a detectable increase in tumor formation. To determine whether mutations in p53 might increase the incidence of tumors associated with the loss of BRCA1 function in mice, we have generated mice carrying mutations at both of these loci. We report here that the presence of a mutant Brca1 allele does not alter survival of either p53^-/- or p53^+/- mice. Although the tumor spectrum was not dramatically altered, an increased incidence of mammary tumors was observed in the Brca1^+/-p53^-/- mice. Four mammary tumors were seen in the Brca1^+/-p53^-/- group whereas only one such tumor was seen among the p53^-/- control group. In addition, although the presence of a mutant Brca1 allele did not alter the survival rate or the incidence of most tumor types in the p53^+/- mice, 5 of the 23 tumors isolated from the Brca1^+/-p53^+/- mice treated with ionizing radiation were of mammary epithelial origin, and 3 of these had lost expression of the wild-type Brca1 gene. In contrast, no such tumors were observed in the irradiated p53^+/- controls. Although the number of mammary tumors observed in these animals is small, these results are suggestive of a role for BRCA1 in mammary tumor formation after exposure to specific DNA damaging agents.

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