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Loss of pSer2448‐mTOR expression is linked to adverse prognosis and tumor progression in ERG‐fusion‐positive cancers
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| Zeitschriftentitel: | International Journal of Cancer |
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| Personen und Körperschaften: | , , , , , , , , , , |
| In: | International Journal of Cancer, 132, 2013, 6, S. 1333-1340 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>Abstract</jats:title><jats:p>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<jats:sup>Ser2448</jats:sup>‐mTOR expression by immunohistochemistry. Moderate to strong p<jats:sup>Ser2448</jats:sup>‐mTOR staining was found in all (<jats:italic>n</jats:italic> = 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<jats:sup>Ser2448</jats:sup>‐mTOR staining was significantly linked to advanced stage (<jats:italic>p</jats:italic> = 0.0027), high‐grade (<jats:italic>p</jats:italic> = 0.0045), nodal positive cancers (<jats:italic>p</jats:italic> = 0.0483), early tumor recurrence (<jats:italic>p</jats:italic> < 0.0001, independently from stage and grade, <jats:italic>p</jats:italic> = 0.0016), lack of Ets‐related gene (ERG) fusion (<jats:italic>p</jats:italic> < 0.0001), reduced androgen receptor expression (<jats:italic>p</jats:italic> < 0.0001 each) and increased cell proliferation (<jats:italic>p</jats:italic> = 0.0092) in all cancers and in the subset of ERG‐fusion‐positive cancers. Loss of p<jats:sup>Ser2448</jats:sup>‐mTOR expression was linked to tumor metastasis (<jats:italic>p</jats:italic> = 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<jats:sup>Ser2448</jats:sup>‐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<jats:sup>Ser2448</jats:sup>‐mTOR expression is a marker for activated AKT/mTOR signaling. Tumors with concomitant PTEN deletion and activated mTOR signaling indicated by loss of p<jats:sup>Ser2448</jats:sup>‐mTOR expression characterize a small (4%) but clinically significant subset of prostate cancers that might optimally benefit from anti‐mTOR therapies.</jats:p> |
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| Umfang: | 1333-1340 |
| ISSN: |
0020-7136
1097-0215 |
| DOI: | 10.1002/ijc.27768 |