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Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions

Oncogene volume 18, pages 2451–2459 (1999)Cite this article

Abstract

Inheritance of germ-line mutant alleles of BRCA1 and BRCA2 confers a markedly increased risk of breast cancer and we have previously reported a higher incidence of p53 mutations in these tumours than in grade matched sporadic tumours. We have now characterized these p53 mutants. The results of these studies identify a novel class of p53 mutants previously undescribed in human cancer yet with multiple occurrences in BRCA-associated tumours which retain a profile of p53-dependent activities in terms of transactivation, growth suppression and apoptosis induction which is close or equal to wild-type. However, these mutants fail to suppress transformation and exhibit gain of function transforming activity in rat embryo fibroblasts. These mutants therefore fall into a novel category of p53 mutants which dissociate transformation suppression from other wild-type functions. The rarity of these mutants in human cancer and their multiple occurrence in BRCA-associated breast tumours suggests that these novel p53 mutants are selected during malignant progression in the unique genetic background of BRCA1- and BRCA2-associated tumours.

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Acknowledgements

We thank K Vousden for pCB6+173L, R Weinberg for pEJ6.6, B Vogelstein for Waf1 luciferase and PIG3 luciferase, J Reid for Bax luciferase, L Buckbinder for IGF BP3 Box A luciferase, Moshe Oren for MDM2 luciferase and Xin Lu for the anti-p21Waf1 antibody. T Crook is a Leopold Muller Fellow. J Waller is funded by US Army grant number DAMD17-94-4066, L Brooks is supported by the Medical Research Council, P Osin by the Gilbert Fellowship and G Parker by the Wellcome Trust. Various parts of the work were supported by the Cancer Research Campaign and Breakthrough Breast Cancer.

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Authors and Affiliations

  1. Institute of Cancer Research, Haddow Laboratories, SM2 5NG, 15 Cotswold Road, Sutton, Surrey, UK

    Paul D Smith, Susan Crossland, Peter Osin, Elizabeth Philp & Mark R Crompton

  2. Ludwig Institute for Cancer Research and Section of Virology and Cell Biology, Imperial College School of Medicine, St Mary's Campus, Norfolk Place, London, W2 1PG, UK

    Gillian Parker & Martin J Allday

  3. Division of Clinical Sciences, London School of Hygiene and Tropical Medicine, Keppel Street, London, W1, UK

    Louise Brooks

  4. Institute of Cancer Research, The Toby Robins Breast Cancer Research Centre, 237 Fulham Road, London, SW3 6JB, UK

    Joanne Waller, Barry A Gusterson & Tim Crook

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  1. Paul D Smith
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Smith, P., Crossland, S., Parker, G. et al. Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions. Oncogene 18, 2451–2459 (1999). https://doi.org/10.1038/sj.onc.1202565

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