Loss of p^Ser2448‐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 followup data was analyzed for p Ser2448 -mTOR expression by immunohistochemistry. Moderate to strong p Ser2448 -mTOR staining was found in all (n 5 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 5 0.0027), high-grade (p 5 0.0045), nodal positive cancers (p 5 0.0483), early tumor recurrence (p < 0.0001, independently from stage and grade, p 5 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 5 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 5 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.

mTOR pathway activation is a favorable prognostic factor in human prostate adenocarcinoma

“…Although mTOR inhibitors blocked mTOR signaling in prostate cancer, no effects on growth reduction, apoptosis and grade change were reported. A previous report on mTOR phosphorylation in prostate cancer identified a small subpopulation of p-mTOR negative patients who may benefit from mTOR inhibition by integrating mTOR phosphorylation, ERG fusion and PTEN mutation status [18]. Yet, this report could not be confirmed by others [19] and was in disagreement with multiple cell biological reports [9, 20].…”

Phospho-mTOR in non-tumour and tumour bladder urothelium: Pattern of expression and impact on urothelial bladder cancer patients

“…It was hypothesised that the downregulation of p-S6 in MI-UBC may be related to the hypoxia-inducible factor-activating hypoxia-resistant microenvironment. Müller et al (57) demonstrated that when comparing between normal and prostate tumour tissues, p-mTOR expression was reduced in the tumour, correlating with adverse clinicopathological features. These results, together with the data of the present study, may reflect the occurrence of alternative mTOR signalling mechanisms that underlie the classical PI3K/Akt activation pathway.…”

BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence

“…The staining intensity (0, 1+, 2+ and 3+) and fraction of positive tumor cells were recorded for each tissue spot. A final immunohistochemistry score was built from these parameters as previously described [67][68][69] . Negative scores indicated the complete absence of staining; weak scores indicated a staining intensity of 1+ in ≤70% of tumor cells or a staining intensity of 2+ in ≤30% of tumor cells; moderate scores indicated a staining intensity of 1+ in >70% of tumor cells, a staining intensity of 2+ in >30% but ≤70% of tumor cells or a staining intensity of 3+ in ≤30% of tumor cells; and strong scores indicated a staining intensity of 2+ in >70% of tumor cells or a staining intensity of 3+ in >30% of tumor cells.…”