Key words: Nuclear receptors; Breast cancer; Liver cancer; Transcription; Pituitary cancer; Translocation; Gene rearrangement; DNA-binding domain; LOH; 3p; 17q

Abstract

Thyroid hormone (triiodothyronine, T3) is a pleiotropic regulator of growth, differentiation and tissue homeostasis in higher organisms that acts through the control of target gene expression. Most, if not all, major T3 actions are mediated by specific high affinity nuclear receptors (TR) which are encoded by two genes, THRA and THRB. Several TRa and TRb receptor isoforms are expressed. Abundant and contradictory literature exist on the relationship between circulating thyroid hormone levels, thyroid diseases and human cancer. In 1986, a connection between TR and cancer became evident when the chicken TRa1 was characterized as the c-erbA proto-oncogene, the cellular counterpart of the retroviral v-erbA oncogene. V-erbA causes erythroleukemias and sarcomas in birds, and hepatocellular carcinomas in transgenic mice. In recent years, many studies have analyzed the presence of quantitative (abnormal levels) or qualitative (mutations) alterations in the expression of THR genes in different types of human neoplasias. While their role in tumor generation or progression is currently unclear, both gross chromosomal and minor mutations (deletions, aberrant splicing, point mutations) and changes in the level of expression of THRA and THRB genes have been found. Together with other in vitro data indicating connections between TR and p53, Rb, cyclin D and other cell cycle regulators and oncogenes, these results suggest that THRA and THRB may be involved in human cancer.

INTRODUCTION

Thyroid hormone (triiodothyronine or T3) is an important regulator of growth, development and differentiation in vertebrates. T3 binds to specific high affinity receptors (thyroid receptors, TR) which belong to the superfamily of nuclear receptors [1]. They function as ligand-modulated transcription factors by binding to sequences known as thyroid hormone response elements (TRE) usually located in the promoter regions of target genes [2,3]. Multiple studies have shown that gene regulation by T3 is modulated by the formation of heterodimers between TR and other members of the receptor superfamily, mainly the retinoic X receptors (RXR), and by subsequent interaction with transcriptional co-regulators (co-activators and co-repressors) and protein complexes [4,5]. Both positive and negative effects of T3 on gene transcription have been described [6,7]. In addition, ligand-activated TRs control gene transcription indirectly by interfering with the function of other transcription factors such as activating protein-1 (AP-1), formed by members of the c-Jun and c-Fos proto-oncogenic proteins [8,9]. A third, less known mechanism of gene regulation by TR is the control of various post-transcriptional processes including splicing, mRNA stability and translation, and protein turn-over [10-12], probably by regulating gene transcription [13]. Finally, non-genomic actions of T3 through rapid mechanisms that remain uncharacterized have been also proposed [14].

The human TRs are encoded by the TRa (THRA) and TRb (THRB) genes, located on human chromosomes 17 and 3, respectively. By alternative splicing and differential promoter usage, these two genes yield several polypeptides [2,3] (Figure 1). TRa1, TRb1 and TRb2 are well-characterized and encode functional products. Another isoform named TRb3 has been cloned from a rat osteosarcoma line and its function is still unknown [15]. Other isoforms such as TRa2 do not bind T3 or dimerize but they can still bind to TREs and inhibit functional receptors in transiently transfected cells [16,17]. In vivo, however, this inhibitory action of TRa2 is not clear as cells expressing high TRa2 levels respond well to T3 [18] and effects of deleting TRa2 expression in mice have been observed [19]. The physiological roles of the non-binding polypeptides TRa2, TRDb3, and two additional truncated TRDa1 and TRDa2 polypeptides [20] remain elusive.

TRs affect gene transcription in four ways: a) induction by hormone-bound TR or b) inhibition by unliganded TR at positive TREs; and c) inhibition by hormone-bound TR or d) activation by unliganded TR at negative TREs. At positive TREs repression of basal transcription by unliganded TR (silencing) is mediated by interaction with co-repressors. TRb2 seems to be the exception, activating transcription even in the absence of hormone [21]. Hormone binding induces a conformational change in TR leading to co-repressors release and subsequent co-activator binding that leads to modification of chromatin structure and transcriptional activation [5,22,23]. The mechanism of transcriptional inhibition at negative TREs is less well understood.

TR are modular proteins (Figure 2). Their most characteristic domains are the highly conserved DNA-binding domain (DBD) which is also involved in dimerization, and the carboxy-terminal ligand binding domain (LBD) responsible for T3 binding, dimerization and interaction with co-regulators [1]. Interaction with the cell basal transcription apparatus depends on the amino-terminal region (Activating Function 1, AF-1), while hormone-dependent transcription regulation (co-repressor and co-activator binding) relies on the extreme carboxy-terminal helix 12 sequence (Activating Function-2, AF-2). However, some isoforms such as rat TRb3 [15] or the chicken TRb0 [24] and TRap40 (translated from an internal AUG codon; [25]) lack the AF-1 region.

In 1986, TRa1 was found to be the cellular counterpart of the retroviral v-erbA oncogene that contributes to the appearance of erythroleukemia and sarcomas in birds [26,27]. v-erbA encodes a highly mutated chicken TRa1 protein that does not bind T3 and acts as a constitutive repressor of T3-regulated genes [28]. V-erbA has weak oncogenic potential itself but potentiates the activity of oncoproteins derived from tyrosine kinases and downstream signal transducers [29,30, reviews]. It enhances the transformed phenotype of cultured erythroblasts and fibroblasts by arresting cellular differentiation and favoring proliferation [29,30, reviews]. Importantly, v-erbA transgenic mice develop hepatocellular carcinomas [31].

In recent years, increasing evidence has suggested that aberrant expression and mutations in THR genes could be associated with carcinogenesis in humans. The focus of this review will be to provide an overview of what we know about the status and expression of THR genes in human cancers.

Thyroid hormone and cancer

Many studies in vitro and in vivo have related thyroid hormones and human cancer since Beatson described the use of thyroid extracts for breast cancer treatment more than a century ago [32]. Abundant data indicate that thyroid status and disease affect tumor formation, growth and metastasis in experimental animals and humans [33,34]. While these studies demonstrated modulation by thyroid hormone of the neoplastic process, no consistent pattern of effects was seen, which suggests confounding factors. Classical studies were mostly focused on the measurement of circulating hormone levels in patients and TR expression was not analysed.

Thyroid hormone receptors in human tumors: cytogenetic alterations

Since the characterization in 1986 of the c-erbA proto-oncogene as the chicken TRa1 gene, a number of studies have analysed the status of TR isoforms in a variety of human neoplasias. Several reports have shown TR alterations and suggested that they could be involved in the development of human cancers.

High frequencies of somatic deletions have been observed in chromosome 3p where THRB lies, in many malignancies including small cell lung, breast, head and neck, renal cell, uterine cervical, ovarian, and testicular cancer, and in uveal melanoma. Some studies propose the inclusion of THRB in the area of genetic deletion [35-37]. Ali and co-workers [38] reported loss of heterozygosity (LOH) on chromosome 3p in 30% of the 84 heterozygous primary breast tumors analysed. The shortest region of homozygosity was located in the 3p21-p25 region and included the THRB locus. 3p21-p25 region also overlaps a 3p deletion characteristic of small-cell lung carcinoma that also includes the THRB gene [39,40]. These results suggested that THRB is a tumor suppressor in human cancers. However, the validity of these two studies was criticized by Huber-Gieseke et al. [41], on the basis that they were done using markers whose location was imprecisely mapped and may hence point to a tumor suppressor gene candidate other than THRB. Huber-Gieseke and colleagues used PCR-based restriction fragment length polymorphism (RFLP) to examine region 3p24 in 19 patients with gastrointestinal tumors and found that only one of them had LOH at this locus, while four patients showed microdeletion of both alleles in 3p24, indicating that this region may be genetically unstable. Lastly, a study by Sisley and co-workers [36] reported LOH of THRB gene in 60% patients with uveal melanoma.

THRA has been studied less. However, the THRA locus undergoes frequent LOH in sporadic breast cancer. Futreal and co-workers [42,43] examined 20 sporadic breast carcinomas for allelic losses of chromosome 17q using microsatellite length polymorphisms. They found that the THRA locus was deleted in 11 out of 14 samples. Moreover, they found a rearrangement of the THRA gene in the BT474 human breast cancer cell line leading to a deletion of exons 8-10 and fusion of exon 7 to a downstream sequence. This deletion also covered the breast and ovarian cancer susceptibility gene BRCA1. However, in an analysis of breast primary tumors, breast cancer cell lines, and lymphoblastoid cell lines from German breast cancer families using single-strand chain polymorphism these authors found no point mutations, thus excluding this locus as a common tumor suppressor gene in breast cancer. Additionally, van de Vijver and colleagues [44] reported amplification and increased expression of the c-erbB2/neu oncogene in 16 out of 95 human breast cancer samples analyzed. In 10 of them, the THRA gene was also co-amplified, although no overexpression was detected. Co-amplification of TRa with c-erbB2/neu has also been described in tubular adenocarcinomas of the stomach [45]. In gastric cancer, Southern analysis has also shown alterations of the THRA gene in 19 out of 39 patients [46]. Interestingly, these alterations were associated with the development of distant metastasis and high expression levels of nm23 gene. A translocation affecting THRA in chromosome 17q was also reported by Dayton and colleagues [47] in acute promyelocytic leukemia and acute poorly differentiated leukemia, indicating that THRA may play a role in the development of these neoplasias in humans.

Thyroid hormone receptors in human cancer: Expression and integrity

Besides large chromosomal defects, altered expression and small mutations on THR genes have also been reported.

Breast cancer.
The status of THR genes in breast cancer has attracted special interest. Hormone dependency of this neoplasia and controversial data on the relation between thyroid status of the patient and the neoplastic illness [34,48,49] have suggested that TR could become a marker and a therapeutic target like the estrogen and progesterone receptors (ER, PR). TRs mediate multiple effects of T3 on the phenotype, proliferation and gene expression of cultured normal mammary epithelial cells [50-52]. However, for a long time little was known about the expression of TR in human breast cancer. Only a few reports described the presence of TR in breast tumors [53-55] and breast cancer cell lines [56,57]. Recently, Li et al [58] reported a variable degree of TRb1 promoter hypermethylation in 11 cases of primary breast cancer, which was concomitant with reduced expression of TRb1 transcripts. Moreover, hypermethylation occurred at the same CpG sites in non-malignant tissue peripheral to the carcinoma in 4 out of 11 cases. The lack of TRb1 nuclear staining, a possible result of biallelic gene inactivation, was observed in 25% (22 of 85) of primary tumors. This report suggests that epigenetic changes in the promoter region of TRb1 may be involved in the inactivation of this gene in early stage breast tumors.

Our group has analyzed the expression and mutational status of the TRa1, TRb1, and TRb2 isoforms in 70 sporadic breast cancers [59]. Alterations in the RNA level of TRa1, TRb1, or both were found in 12 patients, while no expression of TRb2 RNA was detected in either health or tumor breast tissue. These differences in expression were also observed at the protein level in those tumors in which sufficient sample was available. Additionally, tumor-specific truncated TRb1 RNA was found in six patients. Only one tumor carried the corresponding deletion at the genomic DNA level, indicating that the other five abnormal TRb1 transcripts were aberrant splicing products. Interestingly, three of these transcripts shared the same breakpoint, close to the end of exon 6 (following the current nomenclature, see legend to Fig. 1), which indicates the presence of a fragile site or a cryptic splicing site. It is tempting to speculate that neoplastic breast transformation may alter the normal splicing mechanism, producing aberrantly spliced TRb1 RNAs as reported for mdm2 and ERa [60,61]. Our study found no significant correlation between TRb1 alteration and any clinical parameter, although it showed a tendency to associate with early age of onset (<50 years). Abnormalities in THR genes have been described in other human malignancies, although some of the studies did not include a systematic analysis of TR expression.

Liver cancer

Arbuthnot and colleagues [62] studied six hepatocellular carcinomas. They showed that the expression of TRa was higher in the tumor than in normal hepatic tissue, but no gene rearrangements were found. More recently, Lin and colleagues reported a correlation between low levels of the anti-metastatic gene nm23 and overexpression of TRb1 in hepatocellular carcinoma cell lines, suggesting that T3 could be involved in down-regulating this gene [63]. The same authors studied 16 human hepatocellular carcinoma specimens and found truncated TRa1 and TRb1 cDNAs in nine of them [64]. In addition, point mutations in TRa1 and TRb1 were detected in 65% and 76% of the tumors, respectively. These mutations defined two hot spots for TRa1 in amino acid codons 209-228 and 245-256, while no hot-spot was detected in TRb1. Elevated TRb1 protein expression was found in 10 tumors but not in normal livers, whereas the expression of TRa1 was variable among tumors. The in vitro-translated mutant TR proteins showed abnormal binding to DNA. In another study, these authors characterized mutant TRs from human hepatocellular carcinoma cell lines and tumors showing dominant negative activity [65,66]. These mutant proteins can bind TRE but not T3, and thus interfere with the activity of the wild-type receptors. Moreover, the same group recently reported that the dominant negative activity of these mutant TR correlates inversely with the ability of the receptors to interact with the SRC-1 transcriptional co-activator [67].

Thyroid cancer

THR expression has also been studied in normal and malignant thyroid tissue. The levels of TRb RNAs were significantly higher in normal and hyperplastic thyroid tissue than in thyroid tumors, particularly that of TRb2. However, no differences in TRa1 or TRa2 RNA expression were found [68,69]. More recently, Puzianowska-Kuznicka and colleagues [70] analyzed the expression and status of THR in 16 human thyroid papillary cancers. They found that mean expression levels of TRb and TRa RNAs were significantly lower, whereas the protein levels of TRb1 and TRa1 were higher in cancer tissues than in healthy thyroid. In addition, sequencing of cDNAs from these samples revealed 93% of mutations in TRb1 and 62.5% in TRa1. In contrast, no mutations were found in healthy thyroid controls, and only 11% and 22% of thyroid adenomas had mutations in TRb1 and TRa1, respectively. Most of these mutant receptors had lost their transactivation function and exhibited dominant negative function [70]. Recently, Onda et al. [71] found a correlation between expanded microsatellite in the non-coding region of TRa1 and increased TRa1 expression and lower aggressiveness in a series of 30 sporadic thyroid cancers.

Pituitary cancer

Abnormal THR expression has also been reported in tumors of the pituitary gland, which is a target of T3 action in which expression of several hormones including thyrotropin (TSH) and growth hormone is under T3 control. Wang and colleagues [72] reported that TRb1, TRb2 and TRa1 RNAs are expressed in non-functioning adenomas, that TRa1 and TRb1 are specific for prolactinomas, and that TRb1 is detected in acromegalies and FSH-secreting tumors while none of the TR isoforms is expressed in TSH-secreting or ACTH-secreting tumors. Gittoes and colleagues [73] however detected RNA from all TR isoforms in two samples of TSH-secreting pituitary tumors as well as in six normal controls. They found no differences in RNA levels between tumor and control tissue, although TR protein was only detectable in controls, which suggests a post-transcriptional defect in TR RNA processing in TSH-secreting adenomas. Reduced TR expression in these tumors may explain defective negative feedback of T3 on TSH production, which would contribute to uncontrolled tumor growth. These authors also showed that protein levels of all TR isoforms as well as ER were lower in non-functioning tumors of the anterior pituitary than in normal tissue, although the levels of TRb1 and TRb2 (and ER) RNA, but not those of TRa1 and TRa2 were altered [74]. More recently, mutations in both THR genes have been reported in these tumors. McCabe and colleagues [75] analyzed 23 non-functioning pituitary tumors and identified 1 silent change and 3 novel missense mutations in THRA, two in the common region and one TRa2 specific. No mutations were detected in TRb1. Further, Ando and colleagues [76] analyzed five TSH-secreting tumors and reported one mutation in the ligand-binding domain of TRb affecting the same codon that was mutated in two previously identified patients with the syndrome of resistance to thyroid hormone. This mutant TRb had impaired T3 binding and T3-mediated negative TSH regulation. The same group described the expression of an aberrantly spliced TRb2 in a TSH-secreting pituitary tumor. The mutant TRb2 harbors a 45 aminoacid deletion in the sixth exon, which is responsible for the inability to bind T3 and to mediate T3-dependent negative regulation of TSH and glycoprotein hormone a-subunit, and causes also dominant-negative action over wild-type TRb2 in transfected cells [77].

Other cancers

Markowitz and colleagues [78] reported loss or substantial reduction of TRb RNAs in 8 samples of colon carcinoma when compared with non-involved mucosa from the same patients. However, loss of TRb RNA expression was not accompanied by gene deletion. Puzianowska-Kuznicka and colleagues [79] studied THR genes expression in 20 cases of human renal clear cell carcinoma. While TRa RNA was decreased, the TRa1 protein was increased in tumors. TRb1 protein was barely detectable even in those (30%) cancers showing TRb RNA overexpression. In a subsequent study, these authors reported mutations in seven TRb1 and three TRa1 RNAs in a series of 22 renal carcinomas [80]. Two TRb1 mutants had a single mutation but five TRb1 and the three TRa1 had two or three mutations. Most of the mutations were localized in the hormone-binding domain and led to a loss of T3 binding activity or impairment in binding to DNA or both.

Using differential display techniques, Lee et al. [81] identified overexpression of TRa2 in nasopharyngeal carcinoma cell lines as compared to cultured normal nasal epithelial cells. In situ hybridization was used to detect TRa2 expression in clinical biopsies from nasopharyngeal carcinoma patients and non-tumor controls. TRa2 RNA was detected in 4.2% normal nasopharynx epithelium biopsies, in 18.5% primary and in 62.5% recurrent tumors. Additionally, these authors have also shown that forced expression of TRa1 in nasopharyngeal carcinoma cells reduced proliferation, colony-formation ability in agar and the ability to induce tumors in nude mice [82]. These results suggest that TRa1 may function as a tumor suppressor in nasopharyngeal carcinoma tumorigenesis.

Concluding remarks

The role of thyroid hormone in human cancers has yet to be elucidated. From a series of studies reviewed here, alterations in the level of expression and integrity of THR genes occur in different neoplasias (Table1). The biological relevance for the pathogenesis and progression of these processes is however unknown.

The evidence of alterations that affect THR genes, their expression and the activity of their protein products in human cancers makes the analysis of THR genes in human cancer an area of considerable interest. These alterations include LOH, gene rearrangements, hypermethylation, aberrant splicing, point mutations, altered levels of RNA and protein expression, and overexpression of putative inhibitory variants. Given its complex array of biological activities, an altered TR can compromise cell growth or the differentiated phenotype in multiple ways. Most of the mutations or deletions described lead to receptors that could act as dominant negatives over the normal cellular receptors. Many of these mutant TRs bind DNA and could competitively inhibit the access of co-expressed wild type receptors to response elements in their target promoters. In the case of THRB, this is reminiscent of what happens in patients with the syndrome of thyroid hormone resistance, most of whom carry mutations in the THRB gene that produce non-hormone binding polypeptides with dominant negative activity [83,84]. However, patients with this syndrome do not have higher cancer incidence.

Several studies have proposed that TR genes may function as tumor suppressors. However, this hypothesis has not been verified by the analysis of TR knock-out mice since in no case have these animals shown higher cancer incidence [85]. Mutated TR may alter other cellular control systems or signaling pathways. In cancer there are several candidates. Thus, T3 inhibits cyclin D1 expression in mammary epithelial cells [52] though it has the opposite effect in hepatocytes [86]. Emphasizing the complex relation between T3 and cyclin D1, a recent study has proposed that cyclin D1 is a ligand-independent co-repressor for TRs [87]. In neuroblastoma cells and in oligodendrocyte precursor cells T3 increases the expression of various inhibitors of cyclin-dependent kinases [88,89]. In the latter cells T3 has a differentiation-promoting effect that is mediated by the p53 tumor suppressor gene [90]. In addition, chicken TRa1 and human TRb1 interact physically with the p53 protein [91,92]. Wild-type, but not mutant p53 protein represses the T3-dependent transcriptional activation of TRb1 and also blocks the hormone-independent TRa1 transcriptional activity in pituitary GH4C1 cells, while in turn TRb1 inhibits the induction by p53 of several of its target genes [91-93]. The retinoblastoma protein, another tumor suppressor, has been reported to bind and inhibit the activity of Trip230, a transcriptional co-activator of TR [94]. Additionally, in pituitary GH4C1 cells T3 stimulates the expression of mdm2 oncogene, also a target of p53, which exerts a negative feed-back action on this gene [95]. As said before, T3 has an inhibitory effect on AP-1 transcription factor, thought to play important roles in the control of cell proliferation and invasive potential [8,9] and recent studies revealed that TRAP100, a TR co-activator, is a candidate oncogene [96]. The expression of AIB1, other TR co-activator common to steroid receptors, is also altered in some breast cancers [97,98]. Since TR actions are complex and tissue- and time-specific, aberrant expression of the various TR isoforms may have different effects and be associated with different types of tumors and stages of development. It is clear that further studies in larger series of patients are required to establish the significance of THRA and THRB alterations in human cancer and their putative correlation with any clinico-pathological parameter. The evidence presented in this review indicates the need to complement the measurement of blood T3 and T4 concentrations with the analysis of TR expression and integrity in neoplastic patients when studying the relation between thyroid and cancer.

Acknowledgements
We thank Prof. B. Vennström and Dr. D. Forrest for critical reading and discussion of this review, and Robin Rycroft for his valuable assistance in the preparation of the English manuscript. The work of the authors is supported by Grants 08.1/0069/2000 from the Comunidad Autónoma de Madrid and SAF2001-2291 from Ministerio de Ciencia y Tecnología of Spain.

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Figure 1.

Genomic organization and expression of human THRA and THRB genes. Exons are shown as black boxes and numbered on top; introns are represented by lines [15,20,99-101]. For THRA, sequences common to TRa1 and TRa2 are in black. The 3’ end of exon 9 (in white) is skipped in TRa2 and replaced by exon 10 (dotted). The transcription of TRD isoforms is initiated from an internal promoter located within intron 7. Horizontally stripped box within exon 8 indicates sequences specific for TRD isoforms. TRb isoforms are transcribed from three different promoters and have different 5’ sequences. TRb1-specific exons are in grey, those for TRb2 (named “a”) are vertically stripped, and those for TRb3/Db3 (named “A” and “B”) are in diagonal stripes. TRb3 and TRDb3 are transcribed from the same promoter, but exon B is skipped in TRDb3. Positions of the start and stop codons for each TR isoform are shown. The names of the isoforms that encode functional TR are underlined. Although the gene structure corresponding to the region upstream of exon 4 in THRB is not yet characterized, Southern analysis indicates that it is split at least into three exons [99]. Exon structure is well conserved between both THR genes. The DNA-binding domain is split into two exons (4 and 5 for THRA; 5 and 6 for THRB), each containing one zinc-finger motif. In both genes the ligand-binding domain is split into three exons (7, 8, and 9 for THRA; 8, 9 and 10 for THRB), which supports to the idea that both human THR genes derive from a common ancestral gene [102]. In addition, another gene belonging to the nuclear receptor superfamily, ear-1/REV-erbA, overlaps with the 3’ region of THRA in an opposite orientation encoding a protein unrelated to TRs that does not bind hormone [100].

Figure 2.

Functional domains of the thyroid hormone receptors. The DNA-binding domain (DBD) and ligand binding domain (LBD) are highlighted. The DBD is also partially responsible for the dimerization capacity, whereas the LBD overlaps to a great extend with the silencing domain responsible for active transcriptional repression in the absence of thyroid hormone and entails most of the dimerization (Dim) activity. Hormone-independent and -dependent transactivation domains (AF-1 and AF-2) are localized in the receptor aminoterminus and carboxyterminus, respectively. Nuclear localization signal (NLS) sequences mediate the nearly exclusive nuclear localization of the receptor [103], though some studies have described the presence of some forms also into the mitochondria in the rat liver [104].

Table 1.

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