Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer.
Inheritance of one defective BRCA2 allele predisposes humans to breast cancer. To establish a mouse model for BRCA2-associated breast cancer, we generated mouse conditional mutants with BRCA2 and/or p53 inactivated in various epithelial tissues, including mammary-gland epithelium. Although no tumors arose in mice carrying conditional Brca2 alleles, mammary and skin tumors developed frequently in females carrying conditional Brca2 and Trp53 alleles. The presence of one wildtype Brca2 allele resulted in a markedly delayed tumor formation; loss of the wildtype Brca2 allele occurred in a subset of these tumors. Our results show that inactivation of BRCA2 and of p53 combine to mediate mammary tumorigenesis, and indicate that disruption of the p53 pathway is pivotal in BRCA2-associated breast cancer.
Jonkers
J
J
Division of Molecular Genetics and Centre of Biomedical Genetics, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Meuwissen
R
R
van der Gulden
H
H
Peterse
H
H
van der Valk
M
M
Berns
A
A
D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics*; D004195:Disease Models, Animal; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D019656:Loss of Heterozygosity; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic
D024682:BRCA2 Protein