Mammary tumor induction and premature ovarian failure in Apc(Min) mice arenot enhanced by Brca2 deficiency

Inherited BRCA2 mutations predispose individuals to breast cancer and incre ase risk at other sites. Recent studies have suggested a role for the APC I 1307K allele as a low-penetrance breast cancer susceptibility gene that enh ances the phenotypic effects of BRCA1 and BRCA2 mutations. To model the con sequences of inheriting mutant alleles of the BRCA2 and APC tumor suppresso r genes, we examined tumor outcome in C57BL/6 mice with mutations in the Br ca2 and Ape genes. We hypothesized that if the Brca2 and Ape genes were int eracting to influence mammary tumor susceptibility. then mammary tumor inci dence and/or multiplicity would be altered in mice that had inherited mutat ions in both genes. Female and male offspring treated with a single IP inje ction of 50 mg/kg N-ethyl-N-nitrosourea (ENU) at 35 days of age developed m ammary adenoacanthomas by 100 days of age. The female Ape-mutant and Brca2/ Apc double-mutant progeny had mean mammary tumor multiplicities of 6.7 +/- 2.8 and 7.2 +/- 2.7, respectively. compared to wild-type and Brca2-mutant f emales, which had mean mammary tumor multiplicities of 0.1 +/- 0.4 and 0.3 +/- 0.5. respectively. Female ENU-treated Ape-mutant and Brca2/Apc double h eterozygotes were also susceptible to premature ovarian failure. Thus, the inheritance of an Ape mutation predisposes ENU-treated female and male mice to mammary tumors and, in the case of female mice, to ovarian failure. The se results indicate that mammary tumor development in Ape-mutant mice can p rogress independently of ovarian hormones. The Ape mutation-driven phenotyp es were not modified by mutation of Brca2, perhaps because Brca2 acts in a hormonally dependent pathway of mammary carcinogenesis.