Somatic Mutation of TRβ Can Cause a Defect in Negative Regulation of TSH in a TSH-Secreting Pituitary Tumor

Ando, Shinichiro; Sarlis, Nicholas J.; Oldfield, Edward H.; Yen, Paul M.

doi:10.1210/jcem.86.11.7984

Cited by 46 publications

(34 citation statements)

References 35 publications

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“…There was no mutation in the TRβ transcript and no obvious splicing abnormality in the tumor, as reported by Ando et al [17,18]. To investigate the…”

Section: Discussionmentioning

confidence: 76%

Clinical and Molecular Features of a TSH-Secreting Pituitary Microadenoma

et al. 2005

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We describe a case of a thyroid stimulating hormone (TSH)-secreting pituitary microadenoma, and report the systematic gene expression profile of the surgically- removed tumor. A 50-year-old woman was referred to our hospital because she had high TSH, free-T4, and free-T3 levels, and a pituitary tumor that was visualized with magnetic resonance imaging. Her basal TSH level was high even after a high T3 loading dose, and increased following administration of thyroid releasing hormone (TRH) even after administration of a high dose of exogenous T3. Her clinical symptoms and peripheral markers for T3 were responsive to exogenous T3. There was no thyroid hormone receptor (TR) beta gene mutation. The patient was diagnosed with a TSH-secreting pituitary adenoma, and trans-sphenoid surgery was performed. The histologic features and immunophenotype were consistent with a TSH-secreting pituitary adenoma. Reverse transcription-polymerase chain reaction analysis of pituitary hormones, pituitary-specific transcription factors, receptors, and transcriptional cofactors of clinical significance was performed on the removed tumor. The tumor expressed TSH, growth hormone, prolactin, alpha-subunit, pituitary transcription factor-1 (pit-1) but not proopiomelanocortin (POMC), prophet of pit-1 (prop-1) and pituitary cell-restricted T box factor (Tpit). TRbeta and TRH-receptor gene expression was normal. Three steroid receptor coactivators (SRC)-1, SRC-2, and SRC-3 were expressed. Nuclear receptor corepressor (N-CoR)2 was absent in the tumor, whereas nuclear receptor corepressor (N-CoR1) was expressed. Somatostatin receptor type 1 expression was significantly decreased, whereas type 4 receptor was expressed, which are unusual characteristics for pituitary tumors. The gene expression pattern in the tumor might have a role in the clinical features of this case.

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“…There was no mutation in the TRβ transcript and no obvious splicing abnormality in the tumor, as reported by Ando et al [17,18]. To investigate the…”

Section: Discussionmentioning

confidence: 76%

Clinical and Molecular Features of a TSH-Secreting Pituitary Microadenoma

et al. 2005

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“…Thyroid hormone receptors (TRs) play multiple roles in normal differentiation, proliferation, and homeostasis, whereas aberrant TR activity results in endocrine and neoplastic disease (Tenbaum and Baniahmad, 1997;Apriletti et al, 1998;Zhang and Lazar, 2000;Ando et al, 2001;Winter and Signorino, 2001;Cheng, 2003;Gonzalez-Sancho et al, 2003;Yen and Cheng, 2003). Wild-type TRs operate as hormone-regulated transcription factors that bind to specific DNA sequences (denoted thyroid response elements, or TREs) and regulate transcription of adjacent target genes (Mangelsdorf et al, 1995;Glass, 1996;Apriletti et al, 1998;Ribeiro et al, 1998;Beato and Klug, 2000;Zhang and Lazar, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…RTH-mutant TRs remain inappropriately bound to corepressors at physiological T3 concentrations and operate as dominant-negative inhibitors of wild-type TR function. The resulting defects in T3 sensing produce a variety of endocrine defects and, rarely, pituitary neoplasias, but do not typically manifest as overt peripheral neoplasia (Ando et al, 2001;Kamiya et al, 2003). Conversely, somatic mutations in human TRs are found at high frequency in human hepatocellular carcinoma (HCC), renal clear cell cancer (RCCC), and certain thyroid and gastric neoplasia (Lin et al, 1997b(Lin et al, , 1999(Lin et al, , 2001Kamiya et al, 2002;Wang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

Chan

Privalsky

2006

Oncogene

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Aberrant thyroid hormone receptors (TRs) are found in over 70% of the human hepatocellular carcinomas (HCCs) analysed. To better understand the role(s) of these TR mutants in this neoplasia, we analysed a panel of HCC mutant receptors for their molecular properties. Virtually all HCC-associated TR mutants tested retained the ability to repress target genes in the absence of T3, yet were impaired in T3-driven gene activation and functioned as dominant-negative inhibitors of wild-type TR activity. Intriguingly, the HCC TRa1 mutants exerted dominantnegative interference at all T3 concentrations tested, whereas the HCC TRb1 mutants were dominant-negatives only at low and intermediate T3 concentrations, reverting to transcriptional activators at higher hormone levels. The relative affinity for the SMRT versus N-CoR corepressors was detectably altered for several of the HCC mutant TRs, suggesting changes in corepressor preference and recruitment compared to wild type. Several of the TRa HCC mutations also altered the DNA recognition properties of the encoded receptors, indicating that these HCC TR mutants may regulate a distinct set of target genes from those regulated by wild-type TRs. Finally, whereas wild-type TRs interfere with c-Jun/AP-1 function in a T3-dependent fashion and suppress anchorageindependent growth when ectopically expressed in HepG2 cells, at least certain of the HCC mutants did not exert these inhibitory properties. These alterations in transcriptional regulation and DNA recognition appear likely to contribute to oncogenesis by reprogramming the differentiation and proliferative properties of the hepatocytes in which the mutant TRs are expressed.

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“…Somatic mutations of thyroid hormone receptors, increased expression of basic fibroblast growth factor and loss of heterozygosity, and particular polymorphisms of somatostatin receptor type 5 are thought to be involved in tumor pathogenesis (4)(5)(6).…”

Section: Case Reportmentioning

confidence: 99%

Long term treatment of a thyrotropin-secreting microadenoma with somatostatin analogues

Prieto-Tenreiro

Díaz-Guardiola

2010

Arq Bras Endocrinol Metab

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SUMMARYThyrotropin (TSH) secreting pituitary adenomas (TSH-omas) account for < 1% of all pituitary adenomas and are a rare cause of hyperthyroidism. The diagnosis is often made at the stage of macroadenoma because of the aggressive nature of the tumor and due to the fact that patients are mistakenly treated for more common primary hyperthyroidism for a long time. First line therapy is transsphenoidal resection of the tumor, which can cure one-third of the patients completely. However, if surgery is not possible or curative, pituitary radiotherapy and/or somatostatin analogs (SSA) can be useful. We report the case of a 54-year-old woman treated 20 years earlier for a mistakenly suspected primary hyperthyroidism. Given the persistence of symptoms she was studied further and was diagnosed with a thyrotropinoma. Despite the delay in diagnosis and prior thyroid ablation, a microadenoma was found. As transsphenoidal surgery was not considered effective, medical therapy with a somatostatin analogue was initiated. Currently, at four years of follow-up, the patient continues on this treatment and remains euthyroid and asymptomatic. We report a case of successful long-term treatment with SSA, after unsuccessful surgery. Arq Bras Endocrinol Metab. 2010;54(5):502-6 SUMÁRIO Tirotrofinomas (TSH-omas) representam < 1% dos adenomas hipofisários. Eles são uma causa muito rara de hipertireoidismo. O diagnóstico é frequentemente feito na fase de macroadenoma em consequência da natureza agressiva do tumor e do feito de que os doentes são tratados inicialmente por engano e por um longo tempo para hipertireoidismo primário. A terapêutica de primeira linha é a ressecção transesfenoidal do tumor, que cura um terço dos pacientes completamente. Contudo, se a cirurgia não for possível ou curativa, a radioterapia da pituitária e/ou o tratamento com análogos da somatostatina (SSA) podem ser úteis. Relatou-se o caso de uma mulher de 54 anos, tratada há 20 anos por uma suspeita equivocada de hipertireoidismo primário. Dada a persistência dos sintomas, foram realizados mais exames e a paciente foi diagnosticada com TSH-oma. Apesar do diagnóstico tardio e da ablação prévia com iodo radioa tivo, encontrou-se um microadenoma. Como a cirurgia transesfenoidal não foi considerada eficaz, iniciou-se o tratamento da paciente com SSA. Atualmente, após quatro anos de acompanhamento, a paciente continua com o tratamento e permanece eutireoidea e assintomática. Neste artigo, relatou-se a eficácia da terapia medicamentosa com SSA em longo prazo, após cirurgia não eficaz. Arq Bras Endocrinol Metab. 2010;54(5):502-6

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Somatic Mutation of TRβ Can Cause a Defect in Negative Regulation of TSH in a TSH-Secreting Pituitary Tumor

Cited by 46 publications

References 35 publications

Clinical and Molecular Features of a TSH-Secreting Pituitary Microadenoma

Clinical and Molecular Features of a TSH-Secreting Pituitary Microadenoma

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

Long term treatment of a thyrotropin-secreting microadenoma with somatostatin analogues

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