Nature Genetics
17, 423 - 430 (1997)
doi:10.1038/ng1297-423
Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutationFrances Connor1, David Bertwistle1, P. Joseph Mee2, Gillian M. Ross3, Sally Swift1, Elena Grigorieva4, Victor L. J. Tybulewicz2
& Alan Ashworth1, 5, 6
1CRC Centre for Cell and Molecular Biology Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
2Division of Cellular Immunology National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
3Academic Radiotherapy and Oncology Unit, The Institute of Cancer Research, and Royal Marsden Hospital NHS Trust, Sutton, Surrey SM2 5NG, UK
4Division of Developmental Neurobiology National Institute for Medical Research, The Ridge-way, Mill Hill, London NW71AA, UK
5Section of Gene Function and Regulation, Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
6e-mail: alana@icr.ac.uk Germline mutation of the BRCA2 gene carries a high risk of developing breast cancer. To study the function of this gene, we generated a mutation in Brca2 in mice. Unlike other mutations in the Brca2 gene, which are lethal early in embryogenesis when homozygous, some of our homozygous mutant mice survive to adulthood. These animals have a wide range of defects, including small size, improper differentiation of tissues, absence of germ cells and the development of lethal thymic lymphomas. Fibroblasts cultured from Brca2
-/-embryos have a defect in proliferation that may be mediated by over-expression of p53 and p21waf1/Clp1. We show that Brca2 is required for efficient DNA repair, and our results suggest that loss of the p53 checkpoint may be essential for tumour progression triggered by mutations in BRCA2.
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