A tumor suppressor role for thyroid hormone beta receptor in a mouse model of thyroid carcinogenesis.
We have created a knockin mutant mouse by targeting a mutation (PV) into the thyroid hormone receptor beta gene (TRbetaPV mouse). TRbetaPV/PV mice, but not TRbetaPV/+ mice, spontaneously develop follicular thyroid carcinoma. To identify other genetic changes in the TRbeta gene that could also induce thyroid carcinoma, we crossed TRbetaPV mice with TRbeta-/- mice. As TRbetaPV/- mice (mutation of one TRbeta 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 TRbetaPV/- mice was indistinguishable from that in TRbetaPV/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-beta, TNF-alpha, and nuclear factor-kappaB, and also suggested progressive repression of the pathways mediated by the peroxisome proliferator-activated receptor gamma. The patterns in the alteration of these signaling pathways are similar to those observed in TRbeta(PV/PV) mice during thyroid carcinogenesis. These results indicate that in the absence of a wild-type allele, the mutation of one TRbeta 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 TRbeta gene could function as a tumor suppressor gene. Importantly, these findings present the possibility that TRbeta could serve as a novel therapeutic target in thyroid cancer.
Kato
Yasuhito
Y
Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Drive, Room 5128, Bethesda, Maryland 20892-4264, USA.
Ying
Hao
H
Willingham
Mark C
MC
Cheng
Sheue-Yann
SY
D018263:Adenocarcinoma, Follicular / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000818:Animals; D016147:Genes, Tumor Suppressor; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D015398:Signal Transduction; D037042:Thyroid Hormone Receptors beta / Q000172:deficiency / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*
D037042:Thyroid Hormone Receptors beta