The BRAFV600E Oncogene Induces Transforming Growth Factor β Secretion Leading to Sodium Iodide Symporter Repression and Increased Malignancy in Thyroid Cancer

activating mutation BRAF(V600E), is a frequent genetic event in papillary thyroid carcinomas (PTC) that predicts a poor prognosis, leading to loss of sodium/iodide symporter (NIS) expression and subsequent radioiodide-refractory metastatic disease. The molecular basis of such an aggressive behavior induced by BRAF remains unclear. Here, we show a mechanism through which BRAF induces NIS repression and promotes epithelial to mesenchimal transition and invasion based on the operation of an autocrine transforming growth factor (TGF)beta loop. BRAF induces secretion of functional TGF beta and blocking TGF beta/Smad signaling at multiple levels rescues BRAF-induced NIS repression. Although this mechanism is MAP/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK independent, secreted TGF beta cooperates with MEK-ERK signaling in BRAF-induced cell migration, Matrigel invasion, and EMT. Consistent with this process, TGF beta and other key components of TGF beta signaling, such as T beta RII and pSmad2, are overexpressed in human PTC, suggesting a widespread activation of this pathway by locally released TGF beta. Moreover, this high TGF beta/Smad activity is associated with PTC invasion, nodal metastasis, and BRAF status. Interestingly, TGF beta is overexpressed in the invasive front, whereas NIS is preferentially expressed in the central regions of the tumors, suggesting that this negative correlation between TGF beta and NIS occurs locally inside the tumor. Our study describes a novel mechanism of NIS repression in thyroid cancer and provides evidence that TGF beta may play a key role in promoting radioiodide resistance and tumor invasion during PTC progression. [Cancer Res 2009;69(21):8317-25]