Spontaneous and irradiation-induced tumor susceptibility in BRCA2 germline mutant mice and cooperative effects with a p53 germline mutation.
Mutations in both p53 and BRCA2 are commonly seen together in human tumors suggesting that the loss of both genes enhances tumor development. To elucidate this interaction in an animal model, mice lacking the carboxy terminal domain of Brca2 were crossed with p53 heterozygous mice. Females from this intercross were then irradiated with an acute dose of 5 Gy ionizing radiation at 5 weeks of age and compared to nonirradiated controls. We found decreased survival and timing of tumor onsets, and significantly higher overall tumor incidences and prevalence of particular tumors, including stomach tumors and squamous cell carcinomas, associated with the homozygous loss of Brca2, independent of p53 status. The addition of a p53 mutation had a further impact on overall survival, incidence of osteosarcomas and stomach tumors, and tumor latency. The spectrum of tumors observed for this Brca2 germline mouse model suggest that it faithfully recapitulates some human disease phenotypes associated with BRCA2 loss. In addition, these findings include extensive in vivo data demonstrating that germline Brca2 and p53 mutations cooperatively affect animal survivals, tumor susceptibilities, and tumor onsets.
National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27711, USA. mcallis2@niehs.nih.gov
Kimberly A
KA
McAllister
Christopher D
CD
Houle
Jason
J
Malphurs
Toni
T
Ward
N Keith
NK
Collins
William
W
Gersch
Laura
L
Wharey
John C
JC
Seely
Laura
L
Betz
L Michelle
LM
Bennett
Roger W
RW
Wiseman
Barbara J
BJ
Davis
D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics* / Q000502:physiology; D001859:Bone Neoplasms / Q000235:genetics / Q000503:physiopathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000503:physiopathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000235:genetics* / Q000503:physiopathology; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D012516:Osteosarcoma / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D011839:Radiation, Ionizing; D013274:Stomach Neoplasms / Q000235:genetics / Q000503:physiopathology; D015996:Survival Rate; D013997:Time Factors
D024682:BRCA2 Protein; C106711:BRCA2 protein, mouse