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      Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms.

      Human Pathology
      Angiomyolipoma, chemistry, metabolism, pathology, Blotting, Western, Epithelioid Cells, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Kidney Neoplasms, Neoplasms, Connective and Soft Tissue, Oncogene Protein v-akt, analysis, PTEN Phosphohydrolase, Protein Kinases, Ribosomal Protein S6 Kinases, 70-kDa, Signal Transduction, TOR Serine-Threonine Kinases, Tumor Markers, Biological, Tumor Suppressor Proteins, Up-Regulation

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          Abstract

          Angiomyolipoma (AML) belong to a family of tumors known as perivascular epithelioid cell tumors (PEComas) that share a common immunophenotypic profile of muscle and melanocytic differentiation. These tumors are clonal in nature and have a strong association with tuberous sclerosis. Genetic analyses have reported allelic imbalance at the TSC2 locus on 16p13. In the context of non-tuberous sclerosis complex (TSC), non-lymphangioleiomyomatosis-associated AMLs, and non-renal PEComas, the functional status of the TSC2 signaling pathway has not been reported. Studies over the last several years have uncovered a critical role of the TSC1/2 genes in negatively regulating the Rheb/mTOR/p70S6K cascade. Here, we examined the activity of this pathway in sporadic AMLs and PEComas using immunohistochemical and biochemical analyses. We found increased levels of phospho-p70S6K, a marker of mTOR activity, in 15 of 15 non-TSC AMLs. This was accompanied by reduced phospho-AKT expression, a pattern that is consistent with the disruption of TSC1/2 function. Western blot analysis confirmed mTOR activation concurrent with the loss of TSC2 and not TSC1 in sporadic AMLs. Similarly, elevated phospho-p70S6K and reduced phospho-AKT expression was detected in 14 of 15 cases of extrarenal PEComas. These observations provide the first functional evidence that mTOR activation is common to sporadic, non-TSC-related AMLs and PEComas. This suggests the possibility that mTOR inhibitors such as rapamycin may be therapeutic for this class of disease.

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