mTOR pathway overactivation in BRAF mutated papillary thyroid carcinoma

Context: There are several genetic andmolecular evidences suggesting dysregulation of themam-malian target of rapamycin (mTOR) pathway in thyroid neoplasia. Activation of the phosphati-dylinositol-3-kinase/AKTpathwaybyRET/PTCandmutantRAShasalreadybeendemonstrated, but no data have been reported for the BRAFV600E mutation. Objective: The aim of this study was to evaluate the activation pattern of the mTOR pathway in malignant thyroid lesionsandwhether itmaybe correlatedwithknowngenetic alterations, aswell as to explore the mechanisms underlying mTOR pathway activation in these neoplasias. Results: We observed, by immunohistochemical evaluation, an up-regulation/activation of the mTORpathwayproteins in thyroid cancer, particularly in conventional papillary thyroid carcinoma (cPTC). Overactivation of the mTOR signaling was particularly evident in cPTC samples harboring the BRAFV600Emutation. Transfection assays with BRAF expression vectors as well as BRAF knock-downby small interferingRNArevealedapositive associationbetweenBRAFexpressionandmTOR pathway activation, which appears to be mediated by pLKB1 Ser428, and emerged as a possible mechanism contributing to the association between BRAFmutation and mTOR pathway up-reg-ulation.Whenwe evaluated the rapamycin in the growth of thyroid cancer cell lines, we detecte