Novel non-genomic signaling of thyroid hormone receptors in thyroid carcinogenesis

The thyroid hormone receptors (TRs) are transcription factors that mediate the pleiotropic activities of the thyroid hormone, T3. Four T3-binding isoforms, TRα1, TRβ1, TRβ2, and TRβ3, are encoded by two genes, THRA and THRB. Mutations and altered expression of TRs have been reported in human cancers. A targeted germ-line mutation of the Thrβ gene in the mouse leads to spontaneous development of follicular thyroid carcinoma (TRβPV/PV mouse). The TRβPV mutant has lost T3-binding activity and displays potent dominant negative activity. The striking phenotype of thyroid cancer exhibited by TRβPV/PV mice has recently led to the discovery of novel non-genomic actions of TRβPV that contribute to thyroid carcinogenesis. These actions involve direct physical interaction of TRβPV with cellular proteins, namely the regulatory subunit of the phosphatidylinositol 3-kinase (p85α), the pituitary tumor transforming gene (PTTG) and β-catenin, that are critically involved in cell proliferation, motility, migration, and metastasis. Thus, a TRβ mutant (TRβPV), via a novel mode of non-genomic action, acts as an oncogene in thyroid carcinogenesis.