Thyroid hormone receptor mutations in cancer.

The thyroid hormone receptors (TRs) mediate the pleiotropic activities of the thyroid hormone (T3) in growth, development, and differentiation and in maintaining metabolic homeostasis. They are ligand-dependent transcription factors and are members of the steroid hormone/retionic acid receptor superfamily. Two TR genes, alpha and beta, located on human chromosomes 17 and 3, respectively, have been identified. That they are cellular homologs of the retroviral v-erbA oncogene suggests their possible involvement in carcinogenesis. Recent studies showed altered expression of TRs at both the mRNA and protein levels and identified somatic mutations of TRs in several human cancers. Furthermore, male transgenic mice overexpressing v-erbA oncogene develop hepatocellular carcinoma. Importantly, a targeted germline mutation of the TRbeta gene leads to the occurrence of metastatic thyroid carcinoma in homozygous mutant mice. These findings provide evidence to support the critical role of TRs in human cancer.