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A delayed chemically induced tumorigenesis in Brca2 mutant mice

Oncogene volume 23, pages 1896–1901 (2004)Cite this article

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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Abbreviations

DMBA:

7,12-dimethylbenz[a]anthracene

MPA:

medroxyprogesterone acetate

FIAU:

1-[2′-deoxy-2′-fluoro-b-D-arabinofuranosyl]-5-iodouracil

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Acknowledgements

We thank Dr Shih-Jen Hwang for the assistance in the statistical analysis and Dr Chun-Ming Chen for analysing the development of mouse embryos. This work was supported in part by Faculty Achievement Award (MCH), the MD Anderson Breast Cancer Research Program, and grants RO1CA58880 (MCH), RO1CA 77858 (MCH), and Cancer Center Core Grant CA16672 from the NIH.

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  1. Contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas, Houston, TX, USA

    Duen-Hwa Yan, Yong Wen, Li-Kuo Su, Weiya Xia, Shao-Chun Wang, Su Zhang, Dung-Fang Lee, Bill Spohn, Jennifer A Frey & Mien-Chie Hung

  2. Department of Surgical Oncology, The University of Texas, Houston, TX, USA

    Duen-Hwa Yan & Mien-Chie Hung

  3. University of Rochester Center for Aging and Developmental Biology, Rochester, NY, USA

    Lin Gan

  4. Graduate School of Biomedical Sciences, The University of Texas, Houston, TX, USA

    Duen-Hwa Yan, Yong Wen, Li-Kuo Su, Dung-Fang Lee, Jennifer A Frey & Mien-Chie Hung

  5. Department of Breast Medical Oncology, M. D. Anderson Cancer Center, The University of Texas, Houston, TX, USA

    Gabriel N Hortobagyi

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  1. Duen-Hwa Yan
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  2. Yong Wen
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Correspondence to Mien-Chie Hung.

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Yan, DH., Wen, Y., Su, LK. et al. A delayed chemically induced tumorigenesis in Brca2 mutant mice. Oncogene 23, 1896–1901 (2004). https://doi.org/10.1038/sj.onc.1207314

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