Expression of a truncated BRCA1 protein delays lactational mammary development in transgenic mice

MA Brown, H Nicolai, K Howe, T Katagiri, El-Nasir Lalani, KJ Simpson, NW Manning, A Deans, P Chen, KK Khanna, MR Wati, BL Griffiths, CF Xu, GW Stamp, E Solomon

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    25 Citations (Scopus)


    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.
    Original languageEnglish
    Pages (from-to)467-478
    Number of pages12
    JournalTransgenic Research
    Publication statusPublished - 1 Jan 2002


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