{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:32:52Z","timestamp":1771461172340,"version":"3.50.1"},"reference-count":40,"publisher":"The Endocrine Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context:<\/jats:title>\n                  <jats:p>There are several genetic and molecular evidences suggesting dysregulation of the mammalian target of rapamycin (mTOR) pathway in thyroid neoplasia. Activation of the phosphatidylinositol-3-kinase\/AKT pathway by RET\/PTC and mutant RAS has already been demonstrated, but no data have been reported for the BRAFV600E mutation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective:<\/jats:title>\n                  <jats:p>The aim of this study was to evaluate the activation pattern of the mTOR pathway in malignant thyroid lesions and whether it may be correlated with known genetic alterations, as well as to explore the mechanisms underlying mTOR pathway activation in these neoplasias.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results:<\/jats:title>\n                  <jats:p>We observed, by immunohistochemical evaluation, an up-regulation\/activation of the mTOR pathway proteins in thyroid cancer, particularly in conventional papillary thyroid carcinoma (cPTC). Overactivation of the mTOR signaling was particularly evident in cPTC samples harboring the BRAFV600E mutation. Transfection assays with BRAF expression vectors as well as BRAF knockdown by small interfering RNA revealed a positive association between BRAF expression and mTOR pathway activation, which appears to be mediated by pLKB1 Ser428, and emerged as a possible mechanism contributing to the association between BRAF mutation and mTOR pathway up-regulation. When we evaluated the rapamycin in the growth of thyroid cancer cell lines, we detected that cell lines with activating mutations in the MAPK pathway show a higher sensitivity to this drug.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions:<\/jats:title>\n                  <jats:p>We determined that the AKT\/mTOR pathway is particularly overactivated in human cPTC harboring the BRAFV600E mutation. Moreover, our results suggest that the mTOR pathway could be a good target to enhance therapy effects in certain types of thyroid carcinoma, namely in those harboring the BRAFV600E mutation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/jc.2011-2748","type":"journal-article","created":{"date-parts":[[2012,5,2]],"date-time":"2012-05-02T03:44:35Z","timestamp":1335930275000},"page":"E1139-E1149","source":"Crossref","is-referenced-by-count":62,"title":["mTOR Pathway Overactivation in BRAF Mutated Papillary Thyroid Carcinoma"],"prefix":"10.1210","volume":"97","author":[{"given":"Alexandra","family":"Faustino","sequence":"first","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of the University of Porto, Cancer Biology (A.F., J.P.C., H.P., A.S.R., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"}]},{"given":"Joana P.","family":"Couto","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of the University of Porto, Cancer Biology (A.F., J.P.C., H.P., A.S.R., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"},{"name":"Medical Faculty of the University of Porto (J.P.C., H.P., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"}]},{"given":"Helena","family":"P\u00f3pulo","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of the University of Porto, Cancer Biology (A.F., J.P.C., H.P., A.S.R., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"},{"name":"Medical Faculty of the University of Porto (J.P.C., H.P., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"}]},{"given":"Ana Sofia","family":"Rocha","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of the University of Porto, Cancer Biology (A.F., J.P.C., H.P., A.S.R., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"}]},{"given":"Fernando","family":"Pardal","sequence":"additional","affiliation":[{"name":"Department of Pathology (F.P.), Hospital de S\u00e3o Marcos, 4701-965 Braga, Portugal"}]},{"given":"Jos\u00e9 Manuel","family":"Cameselle-Teijeiro","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology (J.M.C.-T.), Clinical University Hospital, SERGAS, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain"}]},{"given":"Jos\u00e9 Manuel","family":"Lopes","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of the University of Porto, Cancer Biology (A.F., J.P.C., H.P., A.S.R., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"},{"name":"Medical Faculty of the University of Porto (J.P.C., H.P., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"},{"name":"Department of Pathology (J.M.L., M.S.-S.), Hospital S\u00e3o Jo\u00e3o, 4200-319 Porto, Portugal"}]},{"given":"Manuel","family":"Sobrinho-Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of the University of Porto, Cancer Biology (A.F., J.P.C., H.P., A.S.R., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"},{"name":"Medical Faculty of the University of Porto (J.P.C., H.P., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"},{"name":"Department of Pathology (J.M.L., M.S.-S.), Hospital S\u00e3o Jo\u00e3o, 4200-319 Porto, Portugal"}]},{"given":"Paula","family":"Soares","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of the University of Porto, Cancer Biology (A.F., J.P.C., H.P., A.S.R., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"},{"name":"Medical Faculty of the University of Porto (J.P.C., H.P., J.M.L., M.S.-S., P.S.), 4200-465 Porto, Portugal"}]}],"member":"80","reference":[{"key":"2020071616351016000_B1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.molmed.2005.06.007","article-title":"An expanding role for mTOR in cancer.","volume":"11","author":"Guertin","year":"2005","journal-title":"Trends Mol 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