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

Research output: Contribution to journalArticlepeer-review

580 Scopus citations


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
Issue number3
StatePublished - 2003
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology
  • General Agricultural and Biological Sciences


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