Endocrine Abstracts

Thyroid cancer is one of the endocrine pathologies whose incidence is increasing, although in general terms it has a good outcome. However, some patients develop aggressive forms that are untreatable and the molecular basis is poorly understood. These aggressive forms are basically well-differentiated thyroid carcinomas that undergo dedifferentiation and poorly differentiated and anaplastic carcinomas. All of them have lost Na/I Symporter (NIS) function leading to radioiodine-resistant metastatic disease. Recent advances have contributed to a better understanding of the pathogenesis of these types of tumors. The genetic changes that activate the signaling cascade RET-RAS-BRAF are well known. The oncogenic BRAF mutation is a frequent genetic event that confers aggressive biological behavior to papillary thyroid cancer and has been associated to increased mortality. We have demonstrated that BRAF impairs NIS function and accordingly causes radioiodine-resistant metastasis. BRAF mediates signal transduction through the MEK-ERK pathway, however, inhibiting this pathway or inhibiting specifically RAF is not enough to induce functional NIS expression or radioiodine uptake. Currently many groups are trying to understand this mechanism to discover new drugs inhibiting BRAF and the MEK-ERK pathway, but with not too much success. This led us to explore alternative mechanisms, and we found that the TGFbeta/Smad signaling is involved in BRAF induced-NIS repression. Moreover, TGFbeta has a strong cooperative effect with MEK-ERK in BRAF-induced epithelial mesenchymal transition (EMT), migration, and invasion. We have observed that TGFbeta controls individual vs. cohesive thyroid cell movement which are key determinants of metastatic dissemination. Finally, although it is well established the regulatory role for microRNAs in cell cycle and proliferation of thyroid cancer, no miRNAs have yet been involved in the formation of radioiodine-resistant metastastic disease. Overall, we are paving the way to better understand the molecular genetics of thyroid cancer that will provide us new approaches for treating this disease.