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

A. P.L. Smith, M. Henze, J. A. Lee, K. G. Osborn, J. M. Keck, D. Tedesco, D. M. Bortner, M. P. Rosenberg, S. I. Reed

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7245-7259
Number of pages15
JournalOncogene
Volume25
Issue number55
DOIs
StatePublished - Nov 23 2006
Externally publishedYes

Keywords

  • Cyclin E
  • Genomic instability
  • Loss of heterozygosity
  • Mammary tumorigenesis
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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