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+l- mice are tumor-free and fertile. Unexpectedly, Brca2+l- 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+l- 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+l+ 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+l- 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.
Original language | English (US) |
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Pages (from-to) | 1896-1901 |
Number of pages | 6 |
Journal | Oncogene |
Volume | 23 |
Issue number | 10 |
DOIs | |
State | Published - Mar 11 2004 |
Externally published | Yes |
Keywords
- Brca2
- Carcinogenesis
- DMBA
- Knockout
- Mammary tumors
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research