Pten dose dictates cancer progression in the prostate

PLoS Biol. 2003 Dec;1(3):E59. doi: 10.1371/journal.pbio.0000059. Epub 2003 Oct 27.

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: Pten(hy/+) > 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 Pten(pc) 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, p27(Kip1), 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Cells, Cultured
  • Crosses, Genetic
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Disease Progression
  • Epithelium / metabolism
  • Fibroblasts / metabolism
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor
  • Hyperplasia / pathology
  • Immunohistochemistry
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Knockout
  • Models, Genetic
  • Mutation
  • PTEN Phosphohydrolase / metabolism
  • PTEN Phosphohydrolase / physiology*
  • Prostate / pathology
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Recombination, Genetic
  • TOR Serine-Threonine Kinases

Substances

  • Cdkn1b protein, mouse
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p27
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse