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

Academic Article
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Overview

related to degree

  • Keck, Jamie, Ph.D. in Biology, Scripps Research 1999 - 2006

authors

  • Smith, A. P. L.
  • Henze, M.
  • Lee, Jiing-Dwan
  • Osborn, K. G.
  • Keck, Jamie
  • Tedesco, D.
  • Bortner, D. M.
  • Rosenberg, M. P.
  • Reed, Steven

publication date

  • November 2006

journal

  • Oncogene  Journal

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.

subject areas

  • Animals
  • Cell Transformation, Neoplastic
  • Cyclin E
  • Genes, p53
  • Immunohistochemistry
  • Loss of Heterozygosity
  • Mammary Glands, Animal
  • Mammary Neoplasms, Animal
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
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Research

keywords

  • cyclin E
  • genomic instability
  • loss of heterozygosity
  • mammary tumorigenesis
  • p53
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Identity

International Standard Serial Number (ISSN)

  • 0950-9232

Digital Object Identifier (DOI)

  • 10.1038/sj.onc.1209713

PubMed ID

  • 16751806
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Additional Document Info

start page

  • 7245

end page

  • 7259

volume

  • 25

issue

  • 55

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