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Pten dose dictates cancer progression in the prostate.

PLoS biology | Dec 31, 2003

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.

Pubmed ID: 14691534 RIS Download

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

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA082328
  • Agency: NCI NIH HHS, Id: CA-84292
  • Agency: NCI NIH HHS, Id: R01 CA-82328
  • Agency: NCI NIH HHS, Id: R01 CA137050
  • Agency: PHS HHS, Id: 92629
  • Agency: NCI NIH HHS, Id: U01 CA084292
  • Agency: NCI NIH HHS, Id: R24CA83084
  • Agency: NCI NIH HHS, Id: R24 CA083084

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