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mTOR pathway overactivation in BRAF mutated papillary thyroid carcinoma

Alexandra Faustino1, Joana P Couto, Helena Pópulo

  • 1Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Cancer Biology, Porto, Portugal.

The Journal of Clinical Endocrinology and Metabolism
|May 3, 2012
PubMed
Abstract

Insights

The mammalian target of rapamycin (mTOR) pathway is overactivated in BRAF V600E-mutated papillary thyroid cancer. This pathway may be a therapeutic target for specific thyroid cancers, enhancing treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The mammalian target of rapamycin (mTOR) pathway is implicated in various cancers.
  • While RET/PTC and RAS mutations activate the phosphatidylinositol-3-kinase/AKT pathway, the role of BRAF V600E in mTOR pathway dysregulation in thyroid neoplasia remains unclear.

Purpose of the Study:

  • To investigate the activation status of the mTOR pathway in malignant thyroid lesions.
  • To determine the correlation between mTOR pathway activation and known genetic alterations, specifically the BRAF V600E mutation.
  • To elucidate the mechanisms driving mTOR pathway activation in thyroid cancer.

Main Methods:

  • Immunohistochemical analysis of mTOR pathway proteins in thyroid cancer tissues.
  • Transfection assays and small interfering RNA (siRNA) knockdown to assess BRAF's role in mTOR activation.
  • Evaluation of rapamycin's effect on thyroid cancer cell lines with MAPK pathway mutations.

Main Results:

  • mTOR pathway proteins were upregulated in thyroid cancer, particularly in conventional papillary thyroid carcinoma (cPTC).
  • Overactivation of mTOR signaling was pronounced in cPTC with the BRAF V600E mutation.
  • BRAF expression positively correlated with mTOR activation, potentially mediated by pLKB1 Ser428, suggesting a mechanism for BRAF mutation-induced mTOR upregulation. Cell lines with MAPK pathway mutations showed increased sensitivity to rapamycin.

Conclusions:

  • The AKT/mTOR pathway is significantly overactivated in human cPTC harboring the BRAF V600E mutation.
  • The mTOR pathway represents a potential therapeutic target for enhancing treatment outcomes in specific thyroid carcinomas, notably those with the BRAF V600E mutation.

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