Despite recent advances, understanding of molecular genetic alterations underlying thyroid carcinogenesis remains unclear. One key question is how dynamic temporal changes in global genomic expression affect carcinogenesis as the disease progresses. To address this question, we used a mouse model that spontaneously develops follicular thyroid cancer similar to human cancer (Thrb (PV/PV) mice). Using complementary DNA microarrays, we compared global gene expression profiles of thyroid tumors of Thrb (PV/PV) mice with the age- and gender-matched thyroids of wild-type mice at 3 weeks and at 2, 4, 6 and 14 months. These time points covered the pathological progression from early hyperplasia to capsular invasion, vascular invasion and eventual metastasis. Microarray data indicated that 462 genes were upregulated (Up-cluster genes) and 110 genes were downregulated (Down-cluster genes). Three major expression patterns (trending up, cyclical and spiking up and then down) and two (trending down and cyclical) were apparent in the Up-cluster and Down-cluster genes, respectively. Functional clustering of tumor-related genes followed by Ingenuity Pathways Analysis identified the transforming growth factor β (TGF β)-mediated network as key signaling pathways. Further functional analyses showed sustained activation of TGFβ receptor-pSMAD2/3 signaling, leading to decreased expression of E-cadherin and increased expression of fibronectin, vimentin, collagens and laminins. These TGFβ-induced changes facilitated epithelial-to-mesenchymal transition, which promotes cancer invasion and migration. Thus, complex temporal changes in gene expression patterns drive thyroid cancer progression, and persistent activation of TGFβ-TGFRβII-pSMAD2/3 signaling leads to EMT, thus promoting metastasis. This study provides new understanding of progression and metastatic spread of human thyroid cancer.