title: Mammary tumor induction and premature ovarian failure in ApcMin mice are not enhanced by Brca2 deficiency.
abstract: 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.
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. bennett42@llnl.gov
authors.forename: L M
authors.initials: LM
authors.lastname: Bennett
authors.forename: K A
authors.initials: KA
authors.lastname: McAllister
authors.forename: T
authors.initials: T
authors.lastname: Ward
authors.forename: J
authors.initials: J
authors.lastname: Malphurs
authors.forename: N K
authors.initials: NK
authors.lastname: Collins
authors.forename: J C
authors.initials: JC
authors.lastname: Seely
authors.forename: B J
authors.initials: BJ
authors.lastname: Davis
authors.forename: R W
authors.initials: RW
authors.lastname: Wiseman
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D000818:Animals; D024682:BRCA2 Protein; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D017491:Genes, APC / Q000235:genetics*; D006579:Heterozygote; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D008679:Metaplasia / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics*; D010049:Ovarian Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; D002273:Carcinogens; D009363:Neoplasm Proteins; D014157:Transcription Factors; D005038:Ethylnitrosourea