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  • Original Paper
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Tumor formation in mice with conditional inactivation of Brca1 in epithelial tissues

Oncogene volume 22, pages 5415–5426 (2003)Cite this article

Abstract

The BRCA1 tumor-suppressor protein has been implicated in the regulation of transcription, DNA repair, proliferation, and apoptosis. BRCA1 is expressed in many proliferative tissues and this is at least in part due to E2F-dependent transcriptional control. In this study, inactivation of a conditional murine Brca1 allele was achieved in a variety of epithelial tissues via expression of the Cre recombinase under the control of a keratin 5 (K5) promoter. The K5 Cre:Brca1 conditional knockout mice exhibited modest epidermal hyperproliferation, increased apoptosis, and were predisposed to developing tumors in the skin, the inner ear canal, and the oral epithelium after 1 year of age. Overexpression of the E2F1 transcription factor in K5 Cre:Brca1 conditional knockout mice dramatically accelerated tumor development. In addition, Brca1 heterozygous female mice that had elevated E2F1 expression developed tumors of the reproductive tract at high incidence. These findings demonstrate that in mice Brca1 functions as a tumor suppressor in other epithelial tissues in addition to the mammary gland. Moreover, inactivation of Brca1 is shown to cooperate with deregulation of the Rb-E2F1 pathway to promote tumorigenesis.

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Acknowledgements

We thank Dr Dennis Johnston for his expert statistical analysis, Pam Blau and Stephanie Clifford for their technical assistance, Dr Lezlee Coghlan, Dale Weiss, and co-workers for animal care, Dr Irma Gimenez-Conti, Nancy Abbey, and co-workers for the immunohistochemistry, Chris Yone and Joi Holcomb for artwork. We also thank Dr Xiaoling Xu for the Brca1 probe for Southern analysis. This work was supported by grants from the National Institute of Health (U01 ES11047 and a T-32 National Service Award Training Grant CA 09480 to TRB).

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Authors and Affiliations

  1. Department of Carcinogenesis, Science Park-Research Division, University of Texas MD Anderson Cancer Center, Smithville, 78957, TX, USA

    Thomas R Berton, Takashi Matsumoto, Claudio J Conti & David G Johnson

  2. Cell and Molecular Biology CIEMAT, Madrid, 28040, Spain

    Angustias Page & José L Jorcano

  3. Laboratory of Biochemistry and Metabolism, National Institute of Diabetes, Digestive and Kidney Diseases, Building 10, Bethesda, 9N105, 20892, MD, USA

    Chu-Xia Deng

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Correspondence to David G Johnson.

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Berton, T., Matsumoto, T., Page, A. et al. Tumor formation in mice with conditional inactivation of Brca1 in epithelial tissues. Oncogene 22, 5415–5426 (2003). https://doi.org/10.1038/sj.onc.1206825

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