Review
Thyroid hormone receptor mutations in cancer

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Abstract

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, α and β, 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 TRβ 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.

Introduction

In 1986 molecular cloning of cDNA for thyroid hormone receptors (TRs) led to the identification of two TR genes, α and β, located on human chromosomes 17 and 3, respectively (Weinberger et al., 1986, Sap et al., 1986). Since then, five major TR isoforms, derived from alternative splicing of the primary transcripts of two TR genes, have been identified (Fig. 1). They belong to a large family of nuclear receptors that include steroid hormone, retinoic acid, Vitamin D, and orphan receptors. TRα1, β1, β2, and β3 differ in the length and amino acid sequence at the amino terminal A/B domain, but bind thyroid hormone (T3) with high affinity to mediate gene regulatory activity. By contrast, TRα2, which differs from other TR isoforms in the C-terminus does not bind T3, and its precise functions have yet to be elucidated. Like other nuclear hormone receptors, these isoforms have an amino-terminal A/B domain, a central DNA-binding domain, and a carboxyl-terminal ligand-binding domain. The amino- and carboxyl-terminal regions contain activation functions I and II, respectively, that are important for transcriptional activation (Yen, 2001, Cheng, 2000, Harvey and Williams, 2002). The expression of TR isoforms is tissue-dependent and developmentally regulated (Yen, 2001, Cheng, 2000).

The regulation of TR transcriptional activity is complex. It depends not only on T3 but also on the type of thyroid hormone response elements (TREs) on the promoters of T3-target genes. The C-terminal region of the ligand-binding domain contains multiple contact surfaces that are important for dimerization with its partners, the retinoid X receptors, and for interactions with corepressors and coactivators (Yen, 2001, Cheng, 2000, McKenna and O’Malley, 2002, Harvey and Williams, 2002). In the absence of T3, TRs via their interacting surfaces associate with corepressors to act as silencers of transcription (Cheng, 2000, Yen, 2001, Harvey and Williams, 2002, McKenna and O’Malley, 2002). Binding of T3 dissociates corepressors from TRs, thereby allowing the liganded-TRs to recruit coactivators for transcriptional activation. A host of TR-associated corepressors and coactivators further recruit other nuclear proteins to form large multiprotein complexes that act to remodel chromatin for transcription repression and activation, respectively (McKenna and O’Malley, 2002, Xu et al., 1999).

Early evidence to suggest that mutated TR could be involved in carcinogenesis came from the discovery that TRα1 is the cellular counterpart of the retroviral v-erbA that is involved in the neoplastic transformation leading to acute erythroleukemia and sarcomas (Sap et al., 1986, Thormeyer and Baniahmad, 1999). The v-erbA oncoprotein itself has weak oncogenic activity, but it augments the transformation activity of other oncoproteins. It is a highly mutated chicken TRα1 that does not bind T3 and loses the ability to activate gene transcription. V-erbA competes with TR for binding to TREs and interferes with the normal transcriptional activity of liganded-TR on several promoters (Yen et al., 1994, Chen and Privalsky, 1993). Thus the v-erbA oncoprotein is thought to repress constitutively, through its dominant negative activity, a certain set of genes that prevent cellular transformation. Indeed, male transgenic mice overexpressing v-erbA develop hepatocellular carcinomas, thereby providing evidence that v-erbA oncoprotein can promote neoplasia in mammals through its dominant negative activity (Barlow et al., 1994).

Other evidence that implicates the involvement of TRs in cancer came from the identification of cyclin D1, a known oncogene product, and p53, a known tumor suppressor, that physically interact with TRβ1. Such interaction results in repression of the transcriptional activity of these nucleoproteins. Yap et al. (1996) showed that the tumor suppressor p53 physically interacts with TRβ1 in vitro and in cultured cells, an interaction that results in the repression of the transcriptional activity of TRβ1 (Bhat et al., 1997). Subsequently, it was found that the transcriptional activity of p53 is repressed owing to the association of p53 with TRβ1 (Barrera-Hernandez et al., 1998). Lin et al. (2002) found that cyclin D1 physically associates with the C-terminal region of the ligand-binding domain of TRβ1 in vitro and in vivo. Cyclin D1 acts to repress the transcriptional activity of TRβ1, α1, and β2 (Lin et al., 2002). These findings suggest that TR could be involved in tumor development and progression by interacting with known and unknown oncogenes and tumor suppressors. This review will first examine the studies to date that show an association of abnormal expression and somatic mutations of TRs with human cancer. The molecular actions of mutant TRβ in carcinogenesis will then be discussed particularly in relation to a unique knock-in mouse model of thyroid cancer.

Section snippets

Liver cancer

In recent years increasing evidence has accumulated to suggest that aberrant expression and mutation of the TR genes could be associated with human neoplasias. In one study, Lin found truncated TRα1 and TRβ1 cDNA in 53% of human hepatocellular carcinomas (9/16 tumors; Lin et al., 1999). Somatic point mutations of TRα1 and TRβ1 were also found in 65% (11/17 tumors) and 76% (13/17 tumors), respectively, of human hepatocellular carcinomas. A high frequency of multiple point mutations was observed

Molecular actions of TRβ mutants in a mouse model of thyroid carcinogenesis

So far the TR mutants identified in human cancers are somatic mutations. Recently, a knock-in mouse that harbors a germline mutation of the TRβ gene was created (Kaneshige et al., 2000). The mutation was targeted to the TRβ gene locus via homologous recombination and the Cre/loxP system (Fig. 2). The mutation is called PV (TRβPV mouse; Fig. 2) after a patient with the mutation who suffers from the disease known as resistance to thyroid hormone (Weiss and Refetoff, 2000). RTH patients manifest

Conclusions and future challenges

Increasing evidence supports the notion that TRs could play an important role in carcinogenesis. The studies cited in this review indicate that a lower and/or aberrant expression and/or somatic mutations of TR are associated with human cancers. These studies suggest that partial loss of normal TR functions due to reduced expression or complete loss of normal TR activities due to mutations and/or aberrant expression provides an opportunity for tumor cells to proliferate, invade, and metastasize.

Acknowledgements

I wish to thank all my colleagues and collaborators who have contributed to the work described in this review.

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