mTOR Pathway Overactivation in BRAF Mutated Papillary Thyroid Carcinoma

• Type: Article in International Scientific Journal
• Date: 2012

Authors

Alexandra Faustino (Author) Other; Joana P Couto (Author) Other; Helena Populo (Author) Other; Ana Sofia Rocha (Author) Other; Fernando Pardal (Author) Other; Jose M Manuel Cameselle Teijeiro (Author) Other; Jose Manuel Lopes (Author) FMUP; Manuel Sobrinho Simoes (Author) FMUP; Paula Soares (Author) FMUP

Journal

Title: Journal of Clinical Endocrinology and Metabolism

Vol. 97

Pages: E1139-E1149

ISSN: 0021-972X

Publisher: Endocrine Society

Indexing

ISI Web of Knowledge - 70 Citations

Scopus - 70 Citations

Scientific classification

FOS: Medical and Health sciences > Clinical medicine

Other information

Authenticus ID: P-002-8CF

DOI: 10.1210/jc.2011-2748

Abstract (EN): Context: 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 knock down 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. (J Clin Endocrinol Metab 97: E1139-E1149, 2012)

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11