Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewThyroid hormone receptors and cancer☆
Highlights
► Mutations of thyroid hormone receptors (TRs) are associated with human cancers. ► Loss of TR normal functions by deletion or mutations contributes to cancer development. ► Mice harboring a homozygous mutation of TRβ spontaneously develop thyroid cancer. ► Nuclear and extra-nuclear actions of a TRβ mutant mediate thyroid carcinogenesis. ► Mouse models of thyroid cancer allow uncovering novel molecular targets for treatment.
Introduction
Molecular cloning of thyroid hormone receptor (TR) cDNA in 1986 ushered in an exciting era in the understanding of the structure, expression, functions, and transcription regulation of TRs [1], [2]. Two human TR genes, THRA and THRB, located on different chromosomes, encode thyroid hormone (T3) binding TR isoforms (TRα1, β1, β2, and β3). Similar to other members of the nuclear receptor superfamily, these TR isoforms have an amino-terminal A/B domain, a central DNA-binding domain, and a carboxyl-terminal ligand-binding domain. These TR isoforms share extensive sequence homology in the DNA and ligand-binding domains, but differ in the length and amino acid sequence at the amino terminal A/B domain. Comparison of X-ray crystallographic structures of rat TRα and human TRβ ligand binding domains shows a close structural similarity [3], [4]. However, there are subtype-dependent differences in the ligand-binding pocket that allow selective recognition of certain ligands [4].
The transcriptional activity of TRs is regulated by multiple mechanisms including the type of thyroid hormone response elements (TREs) located on the promoters of T3 target genes, the tissue- and development-dependent expression of TR isoforms, and a host of nuclear co-repressors and co-activators [5]. In the absence of T3, TRs recruit corepressor proteins, such as nuclear receptor co-repressor 1 (NCOR1) and silencing mediator of retinoid and thyroid hormone receptors (SMRT), and repress the transcription of target genes. In the presence of T3, TRs undergo a conformational change that results in the exchange of co-repressors for co-activators, such as p160/ steroid receptor co-activator-1 (SRC-1) family, to activate transcription of target genes. In addition to transcriptional stimulation, TRs also repress gene expression in a T3-dependent manner by binding to negative TREs [5]. However, recent advances have expanded this T3-dependent corepressor–coactivator exchange model and shown that NCOR1 and SMRT play a role in determining T3-sensitivity in vivo, suggesting that corepressors can be recruited to TR in the presence of T3 [6], [7], [8].
In spite of significant progress in understanding the molecular mechanisms by which TR functions in maintaining normal physiological T3-mediated homeostasis, the roles of TR in human cancers are less well understood. 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 involved in the neoplastic transformation leading to acute erythroleukemia and sarcomas [2], [9]. 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 [10], [11]. Early direct evidence that the v-ERBA oncoprotein can promote neoplasia in mammals through its dominant negative activity was provided by the finding that male transgenic mice over-expressing v-ERBA develop hepatocellular carcinomas [12].
The notion that the loss of TR functions could be involved in the development of human cancers gained further support by association studies. Loss in the expression of the THRB gene because of the truncation/deletion of chromosome 3p where the THRB gene is located was reported in many malignancies including lung, melanoma, breast, head and neck, renal cell, uterine cervical, ovarian, and testicular tumors [13], [14], [15], [16], [17], [18]. The THRA locus undergoes frequent loss of heterozygosity (LOH) in sporadic breast cancer, and rearrangement of the THRA gene has also been reported in leukemia, breast, and stomach cancer [19], [20], [21]. Somatic mutations of TRs have been found in human hepatocellular carcinoma [22], renal clear cell carcinoma [23], [24], breast cancer [25], pituitary tumor [26], [27], and thyroid cancer [28] (Table 1). Many of these TR mutants have lost T3 binding activity and transcription capacity, and some exhibit dominant negative activity [23], [28] (Table 1).
Decreased expression due to silencing of the THRB gene by promoter hyermethylation has been found in human cancer including breast, lung, and thyroid carcinoma [29], [30], [31], [32]. A recent study has provided evidence that the expression of the THRB gene could also be repressed via micro RNAs regulatory mechanisms in papillary thyroid cancer [33]. The findings from these association studies raised the possibility that TRs could function as tumor suppressors in human cancers. However, this possibility could not be directly tested until genetically engineered mouse models became available. This article will briefly review the current mouse models of thyroid cancer caused by the loss of total functional TRs (Thra1−/−Thrb−/− mice) or a targeted homozygous mutation of the Thrb gene (denoted PV; ThrbPV/PV mice) and its derived strains. The altered molecular pathways leading to carcinogenesis due to the PV mutation or loss of TRs will be highlighted and the underlying mechanisms discussed.
Section snippets
Mouse models of thyroid cancer
To test the hypothesis that the loss of normal functions of TRβ contributes to cancer development and progression, several mutant mice have been developed, each of which was designed to explore a specific aspect of the roles TRs play in cancer.
Lessons learned from mouse models of thyroid cancer
The mouse models of thyroid cancer described above allowed elucidation of molecular actions of a mutated TRβ, as well as new insight into how deficiency of TR leads to thyroid carcinogenesis. cDNA microarray analyses indicate complex alterations of multiple pathways in thyroid carcinogenesis of ThrbPV/PV mice [43] suggesting that PV could act as an oncogene via multiple mechanisms to promote cancer progression. The following sections will highlight what has been learned about the roles of TR in
Summary and future directions
Studies of the oncogenic actions of mutant PV in thyroid carcinogenesis of ThrbPV/PV mice have provided direct in vivo evidence to show that TRβ mutations can lead to cancer development. Importantly, novel molecular mechanisms of TRβ mutations in carcinogenesis have been uncovered. PV acts as an oncogene via multiple molecular mechanisms. It can function by interfering with the transcription activity of WT-TR by abnormal repression in the expression of tumor promoters (e.g., PPARγ). PV can also
Acknowledgements
We regret any reference omissions due to length limitation. We wish to thank all colleagues and collaborators who have contributed to the work described in this review. The research described in this review by the authors and their colleagues at National Cancer Institute was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.
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This article is part of a Special Issue entitled Thyroid hormone signalling.