Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene.
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.
McAllister
Kimberly A
KA
Laboratory of Women's Health, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA. mcallis2@niehs.nih.gov
Bennett
L Michelle
LM
Houle
Chris D
CD
Ward
Toni
T
Malphurs
Jason
J
Collins
N Keith
NK
Cachafeiro
Carol
C
Haseman
Joseph
J
Goulding
Eugenia H
EH
Bunch
Donna
D
Eddy
E Mitch
EM
Davis
Barbara J
BJ
Wiseman
Roger W
RW
D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D007178:Inbreeding; D008297:Male; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D017434:Protein Structure, Tertiary
D024682:BRCA2 Protein