Novel oncogenic actions of TRbeta mutants in tumorigenesis.

The thyroid hormone, T3, plays important roles in metabolism, growth, and differentiation. Germline mutations in thyroid hormone receptor beta (TRbeta) have been identified in many individuals with resistance to thyroid hormone, a syndrome of reduced sensitivity to T3. A close association of somatic mutations of TRbeta with several human cancers has become increasingly apparent, but how TRbeta mutants could be involved in the carcinogenesis in vivo has not been addressed. The creation of a mouse model (TRbeta(PV/PV) mouse) that harbors a knockin mutation of TRbeta (denoted TRbetaPV) has facilitated the study of the molecular actions of TRbeta mutants in vivo. The striking phenotype of thyroid cancer and the development of pituitary tumors exhibited by TRbeta(PV/PV) mice have uncovered novel functions of a TRbeta mutant in tumorigenesis. It led to the important findings that the oncogenic action of TRbetaPV is mediated by both genomic and nongenomic actions to alter gene expression and signaling pathways activity.