Human BRCA1 gene rescues the embryonic lethality of Brca1 mutant mice

Authors

  • Jennifer Chandler,

    1. Mouse Cancer Genetics Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland
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  • Peter Hohenstein,

    1. Medical Genetics Center, Department of Human and Clinical Genetics and Pathophysiology of Growth and Differentiation, Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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  • Deborah A. Swing,

    1. Mouse Cancer Genetics Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland
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  • Lino Tessarollo,

    1. Mouse Cancer Genetics Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland
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  • Shyam K. Sharan

    Corresponding author
    1. Mouse Cancer Genetics Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland
    • NCI, P.O. Box B, Frederick, MD 21702
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  • This article is a US Government work and, as such, is in the public domain in the United States of America.

Abstract

Summary: Half of all familial breast cancers are due to mutation in the BRCA1 gene. However, despite its importance, attempts to model BRCA1-induced disease in the mouse have been disappointing. Heterozygous Brca1 knockout mice do not develop mammary tumors and homozygous knockout mice die during embryogenesis from ill-defined causes. Sequence analysis has shown that the coding region, genomic organization, and regulatory sequences of the human and mouse genes are not well conserved. This has raised the question of whether the mouse can serve as an effective model for functional analysis of the human BRCA1 gene. To address this question we have introduced a bacterial artificial chromosome containing the human BRCA1 gene into the germline of Brca1 knockout mice. Surprisingly, we have found that the embryonic lethality of Brca1 knockout mice is rescued by the human transgene. We also show that expression of human BRCA1 transgene mirrors the endogenous murine gene. Our “humanized” transgenic mice can serve as a model system for functional analyses of the human BRCA1 gene. genesis 29:72–77, 2001. Published 2001 Wiley-Liss, Inc.

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