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Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

Oncogene volume 25, pages 7245–7259 (2006)Cite this article

Abstract

Deregulation of cyclin E expression and/or high levels have been reported in a variety of tumors and have been used as indicators of poor prognosis. Although the role that cyclin E plays in tumorigenesis remains unclear, there is evidence that it confers genomic instability when deregulated in cultured cells. Here we show that deregulated expression of a hyperstable allele of cyclin E in mice heterozygous for p53 synergistically increases mammary tumorigenesis more than that in mice carrying either of these markers individually. Most tumors and tumor-derived cell lines demonstrated loss of p53 heterozygosity. Furthermore, this tumor susceptibility is related to the number of times the transgene is induced indicating that it is directly attributable to the expression of the cyclin E transgene. An indirect assay indicates that loss of p53 function is an early event occurring in the mammary epithelia of midlactation mammary glands in which cyclin E is deregulated long before evidence of malignancy. These data support the hypothesis that deregulated expression of cyclin E stimulates p53 loss of heterozygosity by promoting genomic instability and provides specific evidence for this in vivo. Cyclin E deregulation and p53 loss are characteristics often observed in human breast carcinoma.

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Acknowledgements

We thank Margie Chadwell and Anita San Soucie for assistance in histological preparation, Leslie Pfiefer and Cheryl Moffat for help in animal husbandry, Frank van Drogen and Vasco Liberal for review of the manuscript and Charles Spruck and Steve Haase for helpful discussions. APLS was supported by US Army Congressionally Directed Breast Cancer Fellowship DAMD17-00-1-0427. This work was funded by NIH grant RO1-CA78343 to SIR.

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  1. A P L Smith

    Present address: Pathology, Medical Research Council Harwell, Didcot, UK

Authors and Affiliations

  1. Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA

    A P L Smith, M Henze, J M Keck, D Tedesco & S I Reed

  2. Department of Histopathology, Rotherham General Hospital, Rotherham, UK

    J A Lee

  3. Department of Animal Resources, The Scripps Research Institute, La Jolla, CA, USA

    K G Osborn

  4. GlaxoSmithKline, Research Triangle Park, NC, USA

    D M Bortner & M P Rosenberg

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  1. A P L Smith
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Smith, A., Henze, M., Lee, J. et al. Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland. Oncogene 25, 7245–7259 (2006). https://doi.org/10.1038/sj.onc.1209713

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