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.
Yan
Duen-Hwa
DH
Department of Molecular and Cellular Oncology, The University of Texas, Houston, TX, USA.
Wen
Yong
Y
Su
Li-Kuo
LK
Xia
Weiya
W
Wang
Shao-Chun
SC
Zhang
Su
S
Gan
Lin
L
Lee
Dung-Fang
DF
Spohn
Bill
B
Frey
Jennifer A
JA
Hortobagyi
Gabriel N
GN
Hung
Mien-Chie
MC
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