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

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute (Y.K., H.Y., S.-Y.C.), Bethesda, Maryland 20892-4264; and Department of Pathology, Wake Forest University School of Medicine (M.C.W.), Winston-Salem, North Carolina 27157-1072

Address all correspondence and requests for reprints to: Dr. S.-Y. Cheng, Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Drive, Room 5128, Bethesda, Maryland 20892-4264. E-mail: sycheng{at}helix.nih.gov.

We have created a knockin mutant mouse by targeting a mutation (PV) into the thyroid hormone receptor ß gene (TRßPV mouse). TRß^PV/PV mice, but not TRß^PV/+ mice, spontaneously develop follicular thyroid carcinoma. To identify other genetic changes in the TRß gene that could also induce thyroid carcinoma, we crossed TRßPV mice with TRß^–/– mice. As TRß^PV/– mice (mutation of one TRß 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 TRß^PV/– mice was indistinguishable from that in TRß^PV/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-ß, TNF-, and nuclear factor-B, and also suggested progressive repression of the pathways mediated by the peroxisome proliferator-activated receptor . The patterns in the alteration of these signaling pathways are similar to those observed in TRß^PV/PV mice during thyroid carcinogenesis. These results indicate that in the absence of a wild-type allele, the mutation of one TRß 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 TRß gene could function as a tumor suppressor gene. Importantly, these findings present the possibility that TRß could serve as a novel therapeutic target in thyroid cancer.

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