The 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)β loop. BRAF induces secretion of functional TGFβ and blocking TGFβ/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 TGFβ cooperates with MEK-ERK signaling in BRAF-induced cell migration, Matrigel invasion, and EMT. Consistent with this process, TGFβ and other key components of TGFβ signaling, such as TβRII and pSmad2, are overexpressed in human PTC, suggesting a widespread activation of this pathway by locally released TGFβ. Moreover, this high TGFβ/Smad activity is associated with PTC invasion, nodal metastasis, and BRAF status. Interestingly, TGFβ is overexpressed in the invasive front, whereas NIS is preferentially expressed in the central regions of the tumors, suggesting that this negative correlation between TGFβ and NIS occurs locally inside the tumor. Our study describes a novel mechanism of NIS repression in thyroid cancer and provides evidence that TGFβ may play a key role in promoting radioiodide resistance and tumor invasion during PTC progression. [Cancer Res 2009;69(21):8317-25]