A Tumor Suppressor Role for Thyroid Hormone β Receptor in a Mouse Model of Thyroid Carcinogenesis

Abstract

AbstractWe have created a knockin mutant mouse by targeting a mutation (PV) into the thyroid hormone receptor β gene (TRβPV mouse). TRβPV/PV mice, but not TRβPV/+ mice, spontaneously develop follicular thyroid carcinoma. To identify other genetic changes in the TRβ gene that could also induce thyroid carcinoma, we crossed TRβPV mice with TRβ−/− mice. As TRβPV/− mice (mutation of one TRβ allele in the absence of the other wild-type allele) aged, they also spontaneously developed follicular thyroid carcinoma through the pathological progression of hyperplasia, capsular and vascular invasion, anaplasia, and eventually metastasis to the lung, but not to the lymph nodes. The pathological progression of thyroid carcinoma in TRβPV/− mice was indistinguishable from that in TRβPV/PV mice. Analyses of the expression patterns of critical genes indicated activation of the signaling pathways mediated by TSH, peptide growth factors (epidermal growth factor and fibroblast growth factor), TGF-β, TNF-α, and nuclear factor-κB, and also suggested progressive repression of the pathways mediated by the peroxisome proliferator-activated receptor γ. The patterns in the alteration of these signaling pathways are similar to those observed in TRβPV/PV mice during thyroid carcinogenesis. These results indicate that in the absence of a wild-type allele, the mutation of one TRβ allele is sufficient for the mutant mice to spontaneously develop follicular thyroid carcinoma. These results provide, for the first time, in vivo evidence to suggest that the TRβ gene could function as a tumor suppressor gene. Importantly, these findings present the possibility that TRβ could serve as a novel therapeutic target in thyroid cancer.