title: Identification of PHLPP1 as a tumor suppressor reveals the role of feedback activation in PTEN-mutant prostate cancer progression.
abstract: Hyperactivation of the PI 3-kinase/AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, on partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the codeletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN mutant prostate cancer to life-threatening disease.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Muhan
authors.initials: M
authors.lastname: Chen
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Pratt
authors.forename: Martha E
authors.initials: ME
authors.lastname: Zeeman
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Audrey
authors.initials: A
authors.lastname: O'Neill
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martin
authors.forename: Dawid G
authors.initials: DG
authors.lastname: Nowak
authors.forename: Adam
authors.initials: A
authors.lastname: Naguib
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Grace
authors.forename: Jernej
authors.initials: J
authors.lastname: Murn
authors.forename: Nick
authors.initials: N
authors.lastname: Navin
authors.forename: Gurinder S
authors.initials: GS
authors.lastname: Atwal
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: William L
authors.initials: WL
authors.lastname: Gerald
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Newton
authors.forename: Brett S
authors.initials: BS
authors.lastname: Carver
authors.forename: Lloyd C
authors.initials: LC
authors.lastname: Trotman
mesh_terms: D018450:Disease Progression; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D009687:Nuclear Proteins; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human