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A delayed chemically induced tumorigenesis in Brca2 mutant mice.

Authors:
Yan DH, Wen Y, Su LK, Xia W, Wang SC, Zhang S, Gan L, Lee DF, Spohn B, Frey JA, Hortobagyi GN, Hung MC
Affiliation:
Journal:
Oncogene

Abstract

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.

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