A delayed chemically induced tumorigenesis in Brca2 mutant mice.
BRCA2 is a breast cancer susceptibility gene. Germline mutations of BRCA2 account for about 10-30% of familial breast cancer cases. Consistent with its tumor-suppressor activity, BRCA2 plays an important role in DNA repair. To assess the susceptibility of carriers of mutant BRCA2 to tumorigenesis induced by DNA-damaging carcinogens, we generated a Brca2 knockout mouse strain and studied its susceptibility to chemically induced tumorigenesis. Similar to previously reported Brca2 knockout mice, our Brca2-/- embryos die at E8.5-9.5, while the Brca2+/- mice are tumor-free and fertile. Unexpectedly, Brca2+/- mice developed tumors slower than did their wild-type littermates when treated with a potent carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). In vitro experiments showed that Brca2+/- mouse cells and Capan-1 cells, a human pancreatic cancer cell line deficient of BRCA2, were more sensitive to DMBA-induced apoptosis, than were Brca2+/+ mouse cells and a derivative of Capan-1 cells that expressed exogenous wild-type BRCA2, respectively. Our results suggest that enhanced sensitivity of Brca2 mutant cells to DMBA-induced apoptosis at the dose of DMBA we used contributes to the delayed tumorigenesis of Brca2+/- animals. This suggestion may also provide a rational explanation for a previous unexpected finding that cigarette smoking appears to reduce the breast cancer risk of BRCA2 mutation carriers.
Department of Molecular and Cellular Oncology, The University of Texas, Houston, TX, USA.
Duen-Hwa
DH
Yan
Yong
Y
Wen
Li-Kuo
LK
Su
Weiya
W
Xia
Shao-Chun
SC
Wang
Su
S
Zhang
Lin
L
Gan
Dung-Fang
DF
Lee
Bill
B
Spohn
Jennifer A
JA
Frey
Gabriel N
GN
Hortobagyi
Mien-Chie
MC
Hung
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D024682:BRCA2 Protein / Q000172:deficiency*; D002273:Carcinogens / Q000633:toxicity; D005260:Female; D024522:Genes, BRCA2; D015698:Genomic Library; D018095:Germ-Line Mutation; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D013234:Stem Cells
D024682:BRCA2 Protein; D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene