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Cancer Susceptibility of Mice with a Homozygous Deletion in the COOH-Terminal Domain of the Brca2 Gene¹

Laboratory of Women’s Health [K. A. M., C. D. H., T. W., J. M., N. K. C., B. J. D., R. W. W.], Biostatistics Branch [J. H.], and Laboratory of Reproductive Development and Toxicology [E. H. G., E. M. E.], National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709; Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California 94551 [L. M. B.]; Integrated Laboratory Systems, Inc., Durham, North Carolina 27713 [C. C.]; and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599 [D. B.]

Inherited mutations of the human BRCA2 gene confer increased risks for developing breast, ovarian, and several other cancers. Unlike previously described Brca2 knockout mice that display predominantly embryonic lethal phenotypes, we developed mice with a homozygous germ-line deletion of Brca2 exon 27 that exhibit a moderate decrease in perinatal viability and are fertile. We deleted this Brca2 COOH-terminal domain because it interacts directly with the Rad51 protein, contains a nuclear localization signal, and is required to maintain genomic stability in response to various types of DNA damage. These homozygous Brca2-mutant mice have a significantly increased overall tumor incidence and decreased survival compared with their heterozygous littermates. Virgin female mice homozygous for this Brca2 mutation also display an inhibition of ductal side branching in the mammary gland at 6 months of age. Given their substantial viability and cancer predisposition, these mutant mice will be useful to further define the role of the COOH-terminal Brca2 domain in tumorigenesis both in vivo and in vitro.

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