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Mammary Tumor Induction and Premature Ovarian Failure in ApcMin Mice Are Not Enhanced by Brca2 Defi ciency

Laboratory of Molecular Carcinogenesis, National Institutes of Health, Research Triangle Park, NC 27709, bennett42{at}llnl.gov

Kimberly A. Mcallister

Laboratory of Molecular Carcinogenesis, National Institutes of Health, Research Triangle Park, NC 27709

Toni Ward

Laboratory of Molecular Carcinogenesis, National Institutes of Health, Research Triangle Park, NC 27709

Jason Malphurs

Laboratory of Molecular Carcinogenesis, National Institutes of Health, Research Triangle Park, NC 27709

N. Keith Collins

Laboratory of Molecular Carcinogenesis, National Institutes of Health, Research Triangle Park, NC 27709

John C. Seely

Pathco, Inc, Research Triangle Park, NC 27709

Barbara J. Davis

Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709

Roger W. Wiseman

Laboratory of Molecular Carcinogenesis, National Institutes of Health, Research Triangle Park, NC 27709

Inherited BRCA2 mutations predispose individuals to breast cancer and increase risk at other sites. Recent studies have suggested a role for the APC I1307K allele as a low-penetrance breast cancer susceptibility gene that enhances the phenotypic effects of BRCA1 and BRCA2 mutations. To model the consequences of inheriting mutant alleles of the BRCA2 and APC tumor suppressor genes, we examined tumor outcome in C57BL/6 mice with mutations in the Brca2 and Apc genes. We hypothesized that if the Brca2 and Apc genes were interacting to influence mammary tumor susceptibility, then mammary tumor incidence and/or multiplicity would be altered in mice that had inherited mutations in both genes. Female and male offspring treated with a single IP injection of 50 mg/kg N-ethyl-N-nitrosourea (ENU) at 35 days of age developed mammary adenoacanthomas by 100 days of age. The female Apc-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 females, which had mean mammary tumor multiplicities of 0.1 ±0.4 and 0.3 ± 0.5, respectively. Female ENU-treated Apc-mutant and Brca2/Apc double heterozygotes were also susceptible to premature ovarian failure. Thus, the inheritance of an Apc mutation predisposes ENU-treated female and male mice to mammary tumors and, in the case of female mice, to ovarian failure. These results indicate that mammary tumor development in Apc-mutant mice can progress independently of ovarian hormones. The Apc mutation-driven phenotypes were not modified by mutation of Brca2, perhaps because Brca2 acts in a hormonally dependent pathway of mammary carcinogenesis.

Key Words: Mammary ducts • morphology • breast cancer • adenoacanthoma • hormone • Wnt pathway

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Toxicologic Pathology, Vol. 29, No. 1, 117-125 (2001)
DOI: 10.1080/019262301301418928


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