Loss of pSer2448‐mTOR expression is linked to adverse prognosis and tumor progression in ERG‐fusion‐positive cancers. Issue 6 (30th August 2012)

• Record Type: Journal Article
• Authors: Müller, Julia; Ehlers, Arne; Burkhardt, Lia; Sirma, Hüseyin; Steuber, Thomas; Graefen, Markus; Sauter, Guido; Minner, Sarah; Simon, Ronald; Schlomm, Thorsten; Michl, Uwe
• Is Part Of: International journal of cancer. Volume 132:Issue 6(2013:Mar. 15)
• Page Start: 1333
• Page End: 1340
• Publication Date: 2012-08-30
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.27768
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <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<sup>Ser2448</sup>‐mTOR expression by immunohistochemistry. Moderate to strong p<sup>Ser2448</sup>‐mTOR staining was found in all (<italic>n</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<sup>Ser2448</sup>‐mTOR staining was significantly linked to advanced stage (<italic>p</italic> = 0.0027), high‐grade (<italic>p</italic> = 0.0045), nodal positive cancers (<italic>p</italic> = 0.0483), early tumor recurrence (<italic>p</italic> < 0.0001, independently from stage and grade, <italic>p</italic> = 0.0016), lack of Ets‐related gene (ERG) fusion (<italic>p</italic> < 0.0001), reduced androgen receptor expression (<italic>p</italic> < 0.0001 each) and increased cell proliferation (<italic>p</italic> = 0.0092) in all cancers and in the subset of ERG‐fusion‐positive cancers. Loss of p<sup>Ser2448</sup>‐mTOR expression was linked to tumor metastasis (<italic>p</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<sup>Ser2448</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<sup>Ser2448</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<sup>Ser2448</sup>‐mTOR expression characterize a small (4%) but clinically significant subset of prostate cancers that might optimally benefit from anti‐mTOR therapies.</p> </abstract>