Pten dose dictates cancer progression in the prostate.
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.
Trotman
Lloyd C
LC
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, New York, USA.
Niki
Masaru
M
Dotan
Zohar A
ZA
Koutcher
Jason A
JA
Di Cristofano
Antonio
A
Xiao
Andrew
A
Khoo
Alan S
AS
Roy-Burman
Pradip
P
Greenberg
Norman M
NM
Van Dyke
Terry
T
Cordon-Cardo
Carlos
C
Pandolfi
Pier Paolo
PP
D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018450:Disease Progression; D004848:Epithelium / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006965:Hyperplasia / Q000473:pathology; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000378:metabolism / Q000502:physiology*; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011995:Recombination, Genetic; D058570:TOR Serine-Threonine Kinases
C493961:Cdkn1b protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011494:Protein Kinases; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse