Pten dose dictates cancer progression in the prostate

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). ISSN 1545-7885 (Electronic)1544-9173 (Linking)

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DOI: 10.1371/journal.pbio.0000059


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.

Item Type: Paper
Additional Information: PubMed ID: 14691534
Uncontrolled Keywords: phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase protein kinase B protein p27 target of rapamycin kinase tumor suppressor protein Cdkn1b protein, mouse cyclin dependent kinase inhibitor 1B forkhead transcription factor FoxO3 protein, mouse mammalian target of rapamycin protein kinase Pten protein, mouse allele article cancer growth cancer incidence cancer inhibition comparative study dose response down regulation gene activation gene expression profiling gene function gene inactivation gene mutation homologous recombination human molecular genetics pathophysiology prostate carcinoma prostate epithelium protein expression protein function protein localization protein targeting tissue distribution tumor suppressor gene animal biological model cell culture cross breeding disease course epithelium fibroblast gene expression regulation genetic recombination hyperplasia immunohistochemistry male metabolism mouse mouse mutant mutation nuclear magnetic resonance imaging pathology physiology prostate prostate tumor Alleles Animals Cells, Cultured Crosses, Genetic Cyclin-Dependent Kinase Inhibitor p27 Disease Progression Fibroblasts Forkhead Transcription Factors Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor Magnetic Resonance Imaging Mice Mice, Knockout Models, Genetic Prostatic Neoplasms Protein Kinases Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase Recombination, Genetic
Subjects: bioinformatics > genomics and proteomics > annotation > gene expression profiling annotation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
diseases & disorders > cancer > cancer types > prostate cancer
CSHL Authors:
Communities: CSHL labs > Trotman lab
Depositing User: Brian Soldo
Date: 2003
Date Deposited: 23 Mar 2012 16:08
Last Modified: 08 May 2013 16:48
PMCID: PMC270016
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