Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation

Nature Genetics volume 17, pages 423–430 (1997)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Szabo, C.A. & King, M.-C. Inherited breast and ovarian cancer. Hum. Mol. Genet. 4, 1811–1817 (1995).

    Article  CAS  Google Scholar 

  2. Stratton, M.R. & Wooster, R. Hereditary predisposition to breast cancer. Curr. Opin. Genet. Dev. 6, 93–97 (1996).

    Article  CAS  Google Scholar 

  3. Easton, D. Breast cancer genes—e the real risks?. Nature Genet. 16, 210–211 (1997).

    Article  CAS  Google Scholar 

  4. Hall, J.M. et al. Linkage of early−onset familial breast cancer to chromosome 17q21. Scince. 250, 1684–1689 (1990).

    Article  CAS  Google Scholar 

  5. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Scince. 266, 66–71 (1994).

    Article  CAS  Google Scholar 

  6. Wooster, R. et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science 265, 2088–2090 (1994).

    Article  CAS  Google Scholar 

  7. Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 378, 789–792 (1995).

    Article  CAS  Google Scholar 

  8. Futreal, P.A. et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 266, 120–122 (1994).

    Article  CAS  Google Scholar 

  9. Lancaster, J.M. et al. BRCA2 mutations in primary breast and ovarian cancers. Nature Genet. 13, 238–240 (1996).

    Article  CAS  Google Scholar 

  10. Miki, Y., Katagiri, T., Kasumi, F., Yoshimoto, T. & Nakamura, Y. Mutation analysis in the BRCA2 gene in primary breast cancers. Nature Genet. 13, 245–247 (1996).

    Article  CAS  Google Scholar 

  11. Teng, D.H.-F. et al. Low incidence of BRCA2 mutations in breast carcinoma and other cancers. Nature Genet. 13, 241–244 (1996).

    Article  CAS  Google Scholar 

  12. Tavtigian, S.V. et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nature Genet. 12, 333–337 (1996).

    Article  CAS  Google Scholar 

  13. Gayther, S.A. et al. Variation of risks of breast and ovarian cancer associated with different mutations of the BRCA2 gene. Nature Genet. 15, 103–105 (1997).

    Article  CAS  Google Scholar 

  14. Bork, P., Blomberg, N. & Nilges, M. Internal repeats in the BRCA2 protein sequence. Nature Genet. 13, 22–23 (1996).

    Article  CAS  Google Scholar 

  15. Bignell, G., Micklem, G., Stratton, M.R., Ashworth, A. & Wooster, R. The BRC repeats are conserved in mammalian BRCA2 proteins. Hum. Mol. Genet. 6, 53–58 (1997).

    Article  CAS  Google Scholar 

  16. Connor, F. et al. Cloning, chromosomal mapping and expression pattern of the mouse Brca2 gene. Hum. Mol. Genet. 6, 291–300 (1997).

    Article  CAS  Google Scholar 

  17. Sharan, S.K. & Bradley, A., Murine Brca2: sequence, map position, and expression pattern. Genomics 40, 234–241 (1997).

    Article  CAS  Google Scholar 

  18. Rajan, J.V., Wang, M., Marquis, S.T. & Chodosh, L.A. Brca2 is coordinately regulated with Brcal during proliferation and differentiation in mammary epithelial cells. Proc. Natl. Acad. Sci. USA. 93, 13078–13083 (1996).

    Article  CAS  Google Scholar 

  19. Vaughn, J.P. et al. Cell cycle control of BRCA2. Cancer Res. 56, 4590–4594 (1996).

    CAS  PubMed  Google Scholar 

  20. Scully, R. et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell. 88, 265–275 (1997).

    Article  CAS  Google Scholar 

  21. Sharan, S.K. et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature. 386, 804–810 (1997).

    Article  CAS  Google Scholar 

  22. Game, J.C. DMA double−stranded breaks and the RAD50−RAD57 genes in Saccharomyces. Semin.Cancer Biol. 4, 73–83 (1993).

    CAS  PubMed  Google Scholar 

  23. Ivanov, E.L. & Haber, J.E. DNA repair: RAD alert. Curr. Biol. 7, 492–4956 (1997).

    Article  Google Scholar 

  24. Chapman, M.S. & Verma, I.M. Transcriptional activation by Brcal. Nature. 382, 678–679 (1996).

    Article  CAS  Google Scholar 

  25. Milner, J., Ponder, B., Hughes−Davies, L., Seltmann, M. & Kouzarides, T. Transcriptional activation functions in BRCA2. Nature. 386, 772–773 (1997).

    Article  CAS  Google Scholar 

  26. Scully, R. et al. BRCA1 is a component of the RNA polymerase II holoenzyme. Proc. Natl, Acad. Sci. USA 94, 5605–5610 (1997).

    Article  CAS  Google Scholar 

  27. Ludwig, T., Chapman, D.L., Papaioannou, V.E. & Efstratiadis, A. Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brcal, Brca2, Brca1/Brca2, Brca1/p53, and Brca2lp53 nullizygous embryos. Genes Dev. 11, 1226–1241 (1997).

    Article  CAS  Google Scholar 

  28. Suzuki, A. et al. Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev. 11, 1242–1252 (1997).

    Article  CAS  Google Scholar 

  29. Doetschman, T.C., Eistetter, H., Katz, M., Schmidt, W. & Kemler, R. The in vitro development of blastocyst−derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J. Embryol. Exp. Morphol. 87, 27–45 (1985).

    CAS  PubMed  Google Scholar 

  30. Hakem, R. et al. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell 85, 1009–1023 (1996).

    Article  CAS  Google Scholar 

  31. Lu, X. & Lane, D.P. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes? Cell 75, 765–778 (1993).

    Article  CAS  Google Scholar 

  32. Ross, G.M. et al. DNA strand break rejoining defect in xrs-6 is complemented by transfection with the human Ku80 gene. Cancer Res. 55, 1235–1238 (1995).

    CAS  PubMed  Google Scholar 

  33. Gowen, L.C., Johnson, B.L., Latour, A.M., Sulik, K.K. & Koller, B.H. Brcal deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nature Genet. 12, 191–194 (1996).

    Article  CAS  Google Scholar 

  34. Liu, C.Y., Flesken-Nikitin, A., Li, S., Zeng, Y. & Lee, W.H. Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. Genes Dev. 10, 1835–1843 (1996).

    Article  CAS  Google Scholar 

  35. Thorlacius, S. et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nature Genet. 13, 117–119 (1996).

    Article  CAS  Google Scholar 

  36. Montes de Oca Luna, R., Wagner, D.S. & Lozano, G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378, 203–206 (1995).

    Article  CAS  Google Scholar 

  37. Jones, S.N., Roe, A.E., Donehower, L.A. & Bradley, A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378, 206–208 (1995).

    Article  CAS  Google Scholar 

  38. Godley, L.A. et al. Wid−type p53 transgenic mice exhibit altered differentiation of the uteric bud and possess small kidneys. Genes Dev. 10, 836–850 (1996).

    Article  CAS  Google Scholar 

  39. Xu, Y. et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411–2422 (1996).

    Article  CAS  Google Scholar 

  40. Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell. 86, 159–171 (1996).

    Article  CAS  Google Scholar 

  41. Elson, A. et al. Pleiotropic defects in ataxia−telangiectasia protein−deficient mice. Proc. Natl. Acad. Sci. 93, 13084–13809 (1996).

    Article  CAS  Google Scholar 

  42. Meyn, S. Ataxia−telangiectasia and cellular responses to DNA damage. Cancer Res. 55, 5991–6001 (1995).

    CAS  Google Scholar 

  43. Swift, M., Reitnauer, P., Morrell, D. & Chase, C. Breast and other cancers in families with ataxia telangiectasia. N. Engl. J. Med. 316, 1289–1294 (1987).

    Article  CAS  Google Scholar 

  44. Fitzgerald, M.G. et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nature Genet. 15, 307–310 (1997).

    Article  CAS  Google Scholar 

  45. Bishop, D.T. & Hopper, J. AT-attributable risks? Nature Genet. 15, 226 (1997).

    Article  CAS  Google Scholar 

  46. Westphal, C.H. et al. Genetic interactions between atm and p53 influence cellular proiferation and irradiation−induced cell cycle checkpoints. Cancer Res. 57, 1664–1667 (1997).

    CAS  Google Scholar 

  47. Kinzler, K.W. & Vogelstein, B. Gatekeepers and caretakers. Nature. 386, 761–763 (1997).

    Article  CAS  Google Scholar 

  48. Brugarolas, J. & Jacks, T., Indemnity: p53, BRCA and cancer. Nature Med. 3, 721–722 (1997).

    Article  CAS  Google Scholar 

  49. Crook, T., Crossland, S., Crompton, M.R., Osin, P. & Gusterson, B.-A. p53 mutations in BRCA1-associated familial breast cancer. Lancet 350, 638–639 (1997).

    Article  CAS  Google Scholar 

  50. Fukasawa, K., Choi, T., Kuriyama, R., Rulong, S. & Vande Woude, G.F. Abnormal centrosome amplification in the absence of p53. Science. 271, 1744–1747 (1996).

    Article  CAS  Google Scholar 

  51. Tybulewicz, V.L.J., Crawford, C.E., Jackson, P.K., Bronson, R.T. & Mulligan, R.C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell. 65, 1153–1163 (1991).

    Article  CAS  Google Scholar 

  52. Karaplis, A.C. et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone−related peptide gene. Genes Dev. 8, 277–289 (1994).

    Article  CAS  Google Scholar 

  53. Robertson, E.J. Embryo-derived stem cell lines, in Teratocarcinomas and Embryonic Stem Cells. A Practical Approach (ed. Robertson, E.J.) 71–112 (IRL, Oxford, 1987).

    Google Scholar 

  54. Bradley, A. Production and analysis of chimaeric mice, in Teratocarcinomas and Embryonic Stem Cells. A Practical Approach (ed. Robertson, E.J.) 113–151 (IRL, Oxford, 1987).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CRC Centre for Cell and Molecular Biology Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK

    Frances Connor, David Bertwistle, Sally Swift & Alan Ashworth

  2. Division of Cellular Immunology National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    P. Joseph Mee & Victor L. J. Tybulewicz

  3. Academic Radiotherapy and Oncology Unit, The Institute of Cancer Research,

    Gillian M. Ross

  4. Royal Marsden Hospital NHS Trust, Sutton, Surrey, SM2 5NG, UK

    Gillian M. Ross

  5. Division of Developmental Neurobiology National Institute for Medical Research, The Ridge-way, Mill Hill, London, NW71AA, UK

    Elena Grigorieva

  6. Section of Gene Function and Regulation, Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK

    Alan Ashworth

Authors
  1. Frances Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Bertwistle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Joseph Mee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gillian M. Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sally Swift
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elena Grigorieva
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Victor L. J. Tybulewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alan Ashworth
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Connor, F., Bertwistle, D., Mee, P. et al. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat Genet 17, 423–430 (1997). https://doi.org/10.1038/ng1297-423

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1297-423

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing