title: Loss of pSer2448-mTOR expression is linked to adverse prognosis and tumor progression in ERG-fusion-positive cancers.
abstract: Prevalence and clinical significance of mammalian target of rapamycin (mTOR) phosphorylation at the serine 2448 is disputed in prostate cancer. A tissue microarray containing 3,261 prostate cancers and 49 normal prostate samples with clinical follow-up data was analyzed for p(Ser2448)-mTOR expression by immunohistochemistry. Moderate to strong p(Ser2448)-mTOR staining was found in all (n = 49) normal prostate tissues, but was lost in 24% or weak in 29% cancers. Moderate and strong staining was found in 36 and 11% of tumors. Loss of p(Ser2448)-mTOR staining was significantly linked to advanced stage (p = 0.0027), high-grade (p = 0.0045), nodal positive cancers (p = 0.0483), early tumor recurrence (p < 0.0001, independently from stage and grade, p = 0.0016), lack of Ets-related gene (ERG) fusion (p < 0.0001), reduced androgen receptor expression (p < 0.0001 each) and increased cell proliferation (p = 0.0092) in all cancers and in the subset of ERG-fusion-positive cancers. Loss of p(Ser2448)-mTOR expression was linked to tumor metastasis (p = 0.0275) in ERG-fusion-positive cancers only. Molecular subset analysis using pre-existing phosphatase and tensin homolog (PTEN) deletion data revealed that loss of p(Ser2448) -mTOR expression is of prognostic relevance and defines a subpopulation of PTEN-deleted and ERG-fusion-positive cancers with a particular poor outcome. The results of our study strongly suggest that loss of p(Ser2448)-mTOR expression is a marker for activated AKT/mTOR signaling. Tumors with concomitant PTEN deletion and activated mTOR signaling indicated by loss of p(Ser2448)-mTOR expression characterize a small (4%) but clinically significant subset of prostate cancers that might optimally benefit from anti-mTOR therapies.
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Müller
authors.forename: Arne
authors.initials: A
authors.lastname: Ehlers
authors.forename: Lia
authors.initials: L
authors.lastname: Burkhardt
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Sirma
authors.forename: Thomas
authors.initials: T
authors.lastname: Steuber
authors.forename: Markus
authors.initials: M
authors.lastname: Graefen
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.forename: Uwe
authors.initials: U
authors.lastname: Michl
mesh_terms: D018450:Disease Progression; D017353:Gene Deletion; D050939:Gene Fusion; D006801:Humans; D008297:Male; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010766:Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000032:analysis / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human