Brca2 deficiency does not impair mammary epithelium development but promotes mammary adenocarcinoma formation in p53(+/-) mutant mice.
Brca2 is an important tumor suppressor associated with susceptibility to breast cancer. Although increasing evidence indicates that the primary function of Brca2 is to facilitate the repair of DNA damage via the homologous recombination pathway, how Brca2 prevents breast cancer is largely unknown. To study the role of Brca2 specifically in mammary epithelium development, we crossed mice bearing the conditionally deficient allele Brca2(flox9-10) to mouse mammary tumor virus- or whey acidic protein-Cre transgenic lines. Analysis of these animals showed that Brca2 is not required for epithelial expansion in mammary glands of pregnant mice. In addition, examination of mammary gland involution revealed normal kinetics of mammary alveolar cell apoptosis after weaning of litters. Nevertheless, Brca2-deficient mice developed mammary adenocarcinomas after a long latency (average, 1.6 years). Detailed histopathological analysis of four of these tumors demonstrated that three of them showed abnormal p53 protein expression. A mutation in the p53 gene was detected in one case. Moreover, homozygosity versus heterozygosity for the Brca2 mutation heavily skewed the tumor spectrum toward mammary adenocarcinoma development in p53(+/-) mice. Our data indicate that Brca2 is not essential for mammary epithelium development but that Brca2 deficiency and down-regulated p53 expression can work jointly to promote mammary tumorigenesis.
Cheung
Alison M Y
AM
Advanced Medical Discovery Institute, University Health Network, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada.
Elia
Andrew
A
Tsao
Ming-Sound
MS
Done
Susan
S
Wagner
Kay-Uwe
KU
Hennighausen
Lothar
L
Hakem
Razqallah
R
Mak
Tak W
TW
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D024682:BRCA2 Protein / Q000172:deficiency*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D019426:Integrases / Q000378:metabolism; D019656:Loss of Heterozygosity; D008297:Male; D008321:Mammary Glands, Animal / Q000254:growth & development*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011247:Pregnancy; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
D024682:BRCA2 Protein; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases