Role of TSH in the spontaneous development of asymmetrical thyroid carcinoma in mice with a targeted mutation in a single allele of the thyroid hormone-β receptor.
Mutations of the thyroid hormone receptor-β gene (THRB) cause resistance to thyroid hormone (RTH). A mouse model of RTH harboring a homozygous thyroid hormone receptor (TR)-β mutation known as PV (Thrb(PV/PV) mouse) spontaneously develops follicular thyroid cancer (FTC). Similar to RTH patients with mutations of two alleles of the THRB gene, the Thrb(PV/PV) mouse exhibits elevated thyroid hormones accompanied by highly nonsuppressible TSH. However, the heterozygous Thrb(PV/+) mouse with mildly elevated TSH (~2-fold) does not develop FTC. The present study examined whether the mutation of a single allele of the Thrb gene is sufficient to induce FTC in Thrb(PV/+) mice under stimulation by high TSH. Thrb(PV/+) mice and wild-type siblings were treated with propylthiouracil (PTU) to elevate serum TSH. Thrb(PV/+)mice treated with PTU (Thrb(PV/+)-PTU) spontaneously developed FTC similar to human thyroid cancer, but wild-type siblings treated with PTU did not. Interestingly, approximately 33% of Thrb(PV/+)-PTU mice developed asymmetrical thyroid tumors, as is frequently observed in human thyroid cancer. Molecular analyses showed activation of the cyclin 1-cyclin-dependent kinase-4-transcription factor E2F1 pathway to increase thyroid tumor cell proliferation of Thrb(PV/+)-PTU mice. Moreover, via extranuclear signaling, the PV also activated the integrin-Src-focal adhesion kinase-AKT-metalloproteinase pathway to increase migration and invasion of tumor cells. Therefore, mutation of a single allele of the Thrb gene is sufficient to drive the TSH-simulated hyperplastic thyroid follicular cells to undergo carcinogenesis. The present study suggests that the Thrb(PV/+)-PTU mouse model potentially could be used to gain insights into the molecular basis underlying the association between thyroid cancer and RTH seen in some affected patients.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264, USA.
Li
L
Zhao
Xuguang
X
Zhu
Jeong
J
Won Park
Laura
L
Fozzatti
Mark
M
Willingham
Sheue-yann
SY
Cheng
D000483:Alleles; D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics; D013961:Thyroid Gland / Q000473:pathology*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D013963:Thyroid Hormones / Q000097:blood; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D013972:Thyrotropin / Q000235:genetics*
D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D013972:Thyrotropin; D018844:Cyclin-Dependent Kinases