title: mTOR pathway overactivation in BRAF mutated papillary thyroid carcinoma.
abstract: BACKGROUND
  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 BRAF(V600E) mutation.
  
  
  OBJECTIVE
  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.
  
  
  RESULTS
  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 BRAF(V600E) 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.
  
  
  CONCLUSIONS
  We determined that the AKT/mTOR pathway is particularly overactivated in human cPTC harboring the BRAF(V600E) 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 BRAF(V600E) mutation.
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Cancer Biology, Porto, Portugal.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Faustino
authors.forename: Joana P
authors.initials: JP
authors.lastname: Couto
authors.forename: Helena
authors.initials: H
authors.lastname: Pópulo
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Rocha
authors.forename: Fernando
authors.initials: F
authors.lastname: Pardal
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Cameselle-Teijeiro
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Lopes
authors.forename: Manuel
authors.initials: M
authors.lastname: Sobrinho-Simões
authors.forename: Paula
authors.initials: P
authors.lastname: Soares
mesh_terms: D019943:Amino Acid Substitution / Q000502:physiology; D002277:Carcinoma; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D018698:Glutamic Acid / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D020125:Mutation, Missense / Q000502:physiology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012694:Serine / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D014633:Valine / Q000235:genetics
chemical_list: D018698:Glutamic Acid; D012694:Serine; C546842:MTOR protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D014633:Valine