Pten dose dictates cancer progression in the prostate |
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| Authors: | Trotman Lloyd C Niki Masaru Dotan Zohar A Koutcher Jason A Di Cristofano Antonio Xiao Andrew Khoo Alan S Roy-Burman Pradip Greenberg Norman M Van Dyke Terry Cordon-Cardo Carlos Pandolfi Pier Paolo |
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| Affiliation: | 1 Molecular Biology Program, Memorial Sloan–Kettering Cancer Center, Sloan–Kettering Institute New York, New York United States of America;2 Department of Pathology, Memorial Sloan–Kettering Cancer Center, Sloan–Kettering Institute New York, New York United States of America;3 Department of Radiology, Memorial Sloan–Kettering Cancer Center, Sloan–Kettering Institute New York, New York United States of America;4 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill Chapel Hill, North Carolina United States of America;5 Departments of Pathology and Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California Los Angeles, California United States of America;6 Departments of Molecular and Cellular Biology and Urology, Baylor College of Medicine Houston, Texas United States of America |
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| 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+/− > Ptenhy/− (mutants in which we have rescued the embryonic lethality due to complete Pten inactivation) > Pten prostate conditional knockout (Ptenpc) 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. |
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