Pten dose dictates cancer progression in the prostate Journal Article
| Authors: | 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. |
| Article Title: | Pten dose dictates cancer progression in the prostate |
| 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. |
| Keywords: | immunohistochemistry; protein kinase b; protein expression; gene mutation; mutation; disease course; cancer growth; dose response; pathophysiology; comparative study; molecular genetics; nuclear magnetic resonance imaging; magnetic resonance imaging; cancer incidence; protein function; protein localization; forkhead transcription factors; mouse; animal; metabolism; mouse mutant; animals; mice; mice, knockout; allele; homologous recombination; cells, cultured; biological model; gene expression profiling; protein kinases; protein targeting; alleles; gene function; pathology; physiology; prostatic neoplasms; gene expression regulation; cancer inhibition; tumor suppressor gene; gene activation; gene expression regulation, neoplastic; prostate; genetic recombination; cell culture; tissue distribution; recombination, genetic; disease progression; cyclin dependent kinase inhibitor 1b; prostate tumor; hyperplasia; mammalian target of rapamycin; protein p27; cyclin-dependent kinase inhibitor p27; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; proto-oncogene proteins c-akt; pten phosphohydrolase; prostate epithelium; fibroblast; fibroblasts; models, genetic; down regulation; gene inactivation; pten protein, mouse; epithelium; tumor suppressor protein; forkhead transcription factor; protein kinase; genes, tumor suppressor; prostate carcinoma; cdkn1b protein, mouse; cross breeding; crosses, genetic; target of rapamycin kinase; human; male; article; foxo3 protein, mouse |
| Journal Title: | PLoS Biology |
| Volume: | 1 |
| Issue: | 3 |
| ISSN: | 1544-9173 |
| Publisher: | Public Library of Science |
| Date Published: | 2003-12-01 |
| Start Page: | 385 |
| End Page: | 396 |
| Language: | English |
| DOI: | 10.1371/journal.pbio.0000059 |
| PUBMED: | 14691534 |
| PROVIDER: | scopus |
| PMCID: | PMC270016 |
| DOI/URL: | |
| Notes: | Article: E59 -- Export Date: 12 September 2014 -- Source: Scopus |
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