Pten dose dictates cancer progression in the prostate

Lloyd C. Trotman, Masaru Niki, Zohar A. Dotan, Jason A. Koutcher, Antonio Di Cristofano, Andrew Xiao, Alan S. Khoo, Pradip Roy-Burman, Norman M. Greenberg, Terry Van Dyke, Carlos Cordon-Cardo, Pier Paolo Pandolfi

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505 Scopus citations

Abstract

Complete inactivation of the PTEN tumor suppressor gene is extremely common in advanced cancer, including prostate cancer (CaP). However, one PTEN allele is already lost in the vast majority of CaPs at presentation. To determine the consequence of PTEN dose variations on cancer progression, we have generated by homologous recombination a hypomorphic Pten mouse mutant series with decreasing Pten activity: Ptenhy/+ > Pten+/- > Pten hy/- (mutants in which we have rescued the embryonic lethality due to complete Pten inactivation) > Pten prostate conditional knockout (Pten pc) mutants. In addition, we have generated and comparatively analyzed two distinct Ptenpc mutants in which Pten is inactivated focally or throughout the entire prostatic epithelium. We find that the extent of Pten inactivation dictate in an exquisite dose-dependent fashion CaP progression, its incidence, latency, and biology. The dose of Pten affects key downstream targets such as Akt, p27Kip1, mTOR, and FOXO3. Our results provide conclusive genetic support for the notion that PTEN is haploinsufficient in tumor suppression and that its dose is a key determinant in cancer progression.

Original languageEnglish (US)
JournalPLoS biology
Volume1
Issue number3
DOIs
StatePublished - Dec 1 2003
Externally publishedYes

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Trotman, L. C., Niki, M., Dotan, Z. A., Koutcher, J. A., Di Cristofano, A., Xiao, A., Khoo, A. S., Roy-Burman, P., Greenberg, N. M., Van Dyke, T., Cordon-Cardo, C., & Pandolfi, P. P. (2003). Pten dose dictates cancer progression in the prostate. PLoS biology, 1(3). https://doi.org/10.1371/journal.pbio.0000059