Abnormalities Of Thyroid Hormone Receptors In Thyroid Cancer

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The thyroid hormone receptors (TRs) mediate the pleiotropic activities of the thyroid hormone (T3) in growth, development, and differentiation and in maintaining metabolic homeostasis. The two TR genes, and are located on human chromosomes 17 and 3, respectively. Alternative splicing of the primary transcripts gives rise to five major TR isoforms (al, a2, (31, |32, and (33). TRal, TR|31, TR(32, and differ in their lengths and amino acid sequences at the amino terminal A/B domain, but they bind T3 with high affinity to mediate gene regulatory activity. By contrast, TRa2, which differs from the other TR isoforms in the C-terminus, does not bind T3, and its precise functions have yet to be elucidated. The expression of TR isoforms is tissue-dependent and developmentally regulated (1, 2).

Early evidence to suggest that mutated TR could be involved in carcinogenesis came from the discovery that is the cellular counterpart of the retroviral v-erbA

that is involved in the neoplastic transformation leading to acute erythroleukemia and sarcomas (27, 28). The oncogenic role of v-erbA was subsequently demonstrated in mammals in that male transgenic mice overexpressing v-erbA developed hepatocellular carcinoma (29).

In recent years, increasing evidence suggests that aberrant expression and mutation of the TR genes could be associated with human neoplasias. Somatic point mutations of TRal and TR|3l were found in 65% (11/17 tumors) and 76% (13/17 tumors), respectively, of human hepatocellular carcinomas. Many of these mutated TRs have lost T3-binding activity and exhibit aberrant DNA-binding activity (30). Aberrant expression and mutations of TR genes were also found in renal clear cell carcinomas (31). Cloning of TRs from 22 renal clear cell carcinomas and 20 surrounding normal tissues identified somatic mutations in 32% and 14% of cloned TR|3l and TRal cDNAs, respectively (32). Most of the mutations were localized in the hormone-binding domain that leads to loss of T3-binding activity and/or impairment in binding to TREs. Similar to the mutated TRs detected in hepatocellular carcinoma (30, 33), the mutated TRs identified in renal clear cell carcinomas exhibit dominant negative activity (32). These studies suggest that mutated TR plays an important role in the development of these human cancers.

Abnormal expression and somatic mutations of TRs in thyroid cancer

Similar to the expression levels reported for ER, PR, and RAR, an altered expression of TRs was detected in thyroid carcinomas. Comparison of the mRNA expression levels of TR isoforms in normal, hyperplastic, and neoplastic human thyroid tissues indicated that is significantly lower in papillary and follicular carcinomas than it is in normal thyroid. No differences, however, were found in the expression levels of TRal andTRa2 mRNA (34, 35). These findings suggest an association of the reduced expression ofTR|31 mRNA with the development of thyroid carcinomas.

These studies, however, did not determine whether TR|3l, TRal, and TRa2 were altered at the protein level.

In addition to the reduced expression of a lower expression of was found in 16 papillary thyroid carcinomas from Polish patients. The TR(3l and TRal protein levels, however, were higher in cancerous tissues than in nearby healthy tissues, an indication of the complexity in the regulation of TR expression in these tumors (36). To understand the nature of TRs in these papillary thyroid carcinomas, cDNAs were cloned concurrently from both the tumor lesions and the healthy thyroids as controls. Sequence analyses indicated that 93.8% and 62.5% of papillary thyroid carcinomas had mutations in and respectively. In contrast, no mutations were found in healthy thyroid controls, and only 11.1% and 22.2% of thyroid adenomas had mutations in TR|3l and TRal, respectively. Functional analysis indicated that these mutated TRs lose their transactivation function and exhibit dominant negative activity (36).

The reduced expression of in papillary thyroid carcinomas was fur ther confirmed in a more recent study of 16 Japanese patients (37). In contrast to the Polish patients, no amino acid-substitution-mutations were detected in the cloned from these papillary thyroid carcinomas. The reasons for the different propensity in the mutations of the gene in these two groups of patients are not entirely clear. One possibility is that the Polish patients were from the post-Chernobyl population and that radiation exposure is a contributing factor to the high frequency of TR mutations. Indeed, five of the 16 Polish patients with mutated TRs were in their teens when the Chernobyl accident occurred. One of 16 patients received radiation treatment during her childhood because of another disease. The age of other patients ranged from 32-58 years old at the time of the Chernobyl accident (Monika Puzianowska-Kuznicka; personal communication). The validation of this hypothesis would require a cohort study with a larger number of patients and a detailed knowledge of irradiation dose received by the patients.

Another possibility is that the propensity of mutations of in papillary thyroid carcinomas could be affected by the patient's ethnic origin. Genetic variation between different populations occurs frequently. For example, a wide variation in the frequency of RET/PTC rearrangements, a hallmark of papillary thyroid carcinoma, has been reported, ranging from a few percent in Japanese (38) and Saudi Arabian patients (39), to 18.8% in Italian patients (40), to 70% in New Caledonian and 85% in Australian patients (41). The frequency of polymorphisms associated with thyroid diseases also differs in Japanese and Caucasian populations (42). Clarification ofthe issue ofwhether genetic background affects the frequency of mutations in papillary thyroid carcinoma awaits additional analyses in patients with different ethnic origins.

Germline mutations of the TR|i gene in thyroid cancer: lessons learned from a unique mouse model of thyroid carcinogenesis

So far, the TR mutants identified in human cancers including thyroid carcinoma are somatic mutations. A knock-in mouse that harbors a gerrnline mutation of the gene has been created (43). The mutation was targeted to the gene locus

Table 1. Histologic progression of thyroid neoplasia in 5—14 month-old TR|3PV/Pvm,ce

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