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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.

Pubmed ID: 14981540


  • Yan DH
  • Wen Y
  • Su LK
  • Xia W
  • Wang SC
  • Zhang S
  • Gan L
  • Lee DF
  • Spohn B
  • Frey JA
  • Hortobagyi GN
  • Hung MC



Publication Data

March 11, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: CA16672
  • Agency: NCI NIH HHS, Id: R01CA 77858
  • Agency: NCI NIH HHS, Id: R01CA58880

Mesh Terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Apoptosis
  • BRCA2 Protein
  • Carcinogens
  • Female
  • Genes, BRCA2
  • Genomic Library
  • Germ-Line Mutation
  • Mammary Neoplasms, Experimental
  • Mice
  • Mice, Knockout
  • Stem Cells