Pten Dose Dictates Cancer Progression in the Prostate

By L. Trotman, M. Niki, Z. Dotan, J. Koutcher, A. Di Cristofano, A. Xiao, A. Khoo, P. Roy-burman, N. Greenberg, T. V. Dyke and 2 more. PLoS Biology, 2003

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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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5e3da798a5e70de6e3425160db63eaaa29b75f4b

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Citations in the corpus

Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. (2011, background): “The GEM Cancer Cell 19, 575–586, May 17, 2011 ª2011 Elsevier Inc. 583 models of human prostate cancer (PB-MYC and Ptenlox/lox PB-Cre) have been described previously (Ellwood-Yen et al., 2003; Trotman et al., 2003).”
Tenets of PTEN tumor suppression. (2008, background): “However, transgenic models with prostate-specific overexpression of a constitutively active AKT develop only localized and, for the most part, preneoplastic lesions (Majumder et al., 2003; Trotman et al., 2003).”
Targeting PI3K signalling in cancer: opportunities, challenges and limitations (2009, background): “Homozygous deletion of Pten in the prostate epithelium leads to aggressive prostate carcinom”
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism (2006, result): “This model is consistent with findings from an elegant study showing that progressive reduction in Pten gene dosage results in increasingly aggressive mouse prostate neoplasi”
PTEN loss in the continuum of common cancers, rare syndromes and mouse models (2011, unknown): “The use of Pten hypomorphic alleles demonstrated that decreasing PTEN levels correlate with increased progression of prostate tumours in the mous”
BRafV600E cooperates with Pten silencing to elicit metastatic melanoma (2009, background): “One allele ( Pten loxP-neo ) conditionally deletes Pten exons 4 and 5 (ref”
Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate (2009, background): “We have previously established a critical role for Pten loss in prostate tumorigenesi”
Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs (2011, unknown): “…(2) subtle changes in PTEN dose dictate critical outcomes in tumor initiation and progression in vivo (Alimonti et al., 2010; Berger et al., 2011; Trotman et al., 2003), and (3) numerous microRNAs have beenvalidatedasPTENregulators, including theproto-oncogenic miR-106b 25 cluster that is…”
Subtle variations in Pten dose determine cancer susceptibility (2010, background): “It has been hypothesized that subtle variations in TSG expression can promote cancer developmen”
Molecular genetics of prostate cancer: new prospects for old challenges. (2010, background): “Trotman et al. 2003; Wang et al. 2003 Selected models represent the range of phenotypes, transforming events, and allelic alterations that are available for studying prostate cancer in GEM mice. of chemopreventive agents.”
miR-19 is a key oncogenic component of mir-17-92. (2009, background): “…tumor suppressor whose dosage proportionally impacts its tumor suppressor activity and inversely correlates with tumor progression in a cell type-dependent manner Cold Spring Harbor Laboratory Press on February 7, 2024 - Published by genesdev.cshlp.org Downloaded from (Trotman et al. 2003).”
NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. (2007, unknown): “IHC of Mouse Prostates IHC was carried out with the automated staining processor (Ventana Medical Systems, AZ) for mouse prostates as previously described (Trotman et al., 2003) using the following antibodies: rabbit antip-Akt (Ser473, IHC-specific; Cell Signaling Technology, Inc.”
Ubiquitination regulates PTEN nuclear import and tumor suppression. (2007, methodology): “, 2006) or, alternatively, in the context of genetically engineered reduction of Pten expression just below heterozygosity (Trotman et al., 2003).”