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Expression of a Truncated Brca1 Protein Delays Lactational Mammary Development in Transgenic Mice

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Abstract

To address the hypothesis that certain disease-associated mutants of the breast-ovarian cancer susceptibility gene BRCA1 have biological activity in vivo, we have expressed a truncated Brca1 protein (trBrca1) in cell-lines and in the mammary gland of transgenic mice. Immunofluorescent analysis of transfected cell-lines indicates that trBRCA1 is a stable protein and that it is localized in the cell cytoplasm. Functional analysis of these cell-lines indicates that expression of trBRCA1 confers an increased radiosensitivity phenotype on mammary epithelial cells, consistent with abrogation of the BRCA1 pathway. MMTV-trBrca1 transgenic mice from two independent lines displayed a delay in lactational mammary gland development, as demonstrated by altered histological profiles of lobuloalveolar structures. Cellular and molecular analyses indicate that this phenotype results from a defect in differentiation, rather than altered rates of proliferation or apoptosis. The results presented in this paper are consistent with trBrca1 possessing dominant-negative activity and playing an important role in regulating normal mammary development. They may also have implications for germline carriers of BRCA1 mutations.

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Authors and Affiliations

  1. Cancer Genetics Laboratory, Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, London, SE1 9RT, UK

    Melissa A. Brown, Hans Nicolai, Kathy Howe, Toyomasa Katagiri, Chun-Fang Xu & Ellen Solomon

  2. Imperial Cancer Research Fund, Lincoln's Inn Fields, London, WC2A 3PX, UK

    Melissa A. Brown, Hans Nicolai, Kathy Howe & Beatrice L. Griffiths

  3. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, 3052, Australia

    Melissa A. Brown, Kaylene J. Simpson, Nathan W. Manning & Andrew Deans

  4. Department of Biochemistry and Molecular Biology, University of Queensland, St. Lucia, 4072, Australia

    Melissa A. Brown & Mas Rina Wati

  5. Department of Histopathology, Imperial College School of Medicine, The Hammersmith Hospital Campus, London, W12 0NN, UK

    El-Nasir Lalani & Gordon W. H. Stamp

  6. Queensland Institute of Medical Research, Herston, 4006, Australia

    Phil Chen & Kum Kum Khanna

Authors
  1. Melissa A. Brown
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  2. Hans Nicolai
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  3. Kathy Howe
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  4. Toyomasa Katagiri
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  5. El-Nasir Lalani
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  8. Andrew Deans
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  9. Phil Chen
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  12. Beatrice L. Griffiths
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  13. Chun-Fang Xu
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  14. Gordon W. H. Stamp
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  15. Ellen Solomon
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Correspondence to Melissa A. Brown.

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Brown, M.A., Nicolai, H., Howe, K. et al. Expression of a Truncated Brca1 Protein Delays Lactational Mammary Development in Transgenic Mice. Transgenic Res 11, 467–478 (2002). https://doi.org/10.1023/A:1020348025139

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  • DOI: https://doi.org/10.1023/A:1020348025139