title: Functionally impaired TR mutants are present in thyroid papillary cancer.
abstract: TRs are transcription factors that regulate cell proliferation, differentiation, and apoptosis. They are cellular homologs of the transcriptionally inactive viral oncogene v-erbA. We tested the hypothesis that the functions of TRs could be impaired in cancer tissues as a result of aberrant expression and/or somatic mutations. As a model system, we selected human thyroid papillary cancer, in which the most common abnormalities, RET/papillary thyroid cancer rearrangements (fusion of RET kinase domain to the activating domains of other genes), were found in 40--45% of cases. We found that the mean expression levels of TR beta mRNA and TR alpha mRNA were significantly lower, whereas the protein levels of TR beta 1 and TR alpha 1 were higher in cancer tissues than in healthy thyroid. Sequencing of TR beta 1 and TR alpha 1 cDNAs, cloned from 16 papillary cancers, revealed that mutations affected receptor amino acid sequences in 93.75% and 62.5% of cases, respectively. In contrast, no mutations were found in healthy thyroid controls, and only 11.11% and 22.22% of thyroid adenomas had such TR beta 1 or TR alpha 1 mutations, respectively. The majority of the mutated TRs lost their trans-activation function and exhibited dominant negative activity. These findings suggest a possible role for mutated thyroid hormone receptors in the tumorigenesis of human papillary thyroid carcinoma.
authors.affiliation: Department of Endocrinology, Medical Research Center, Polish Academy of Sciences, 02-097 Warsaw, Poland. monika@amwaw.edu.pl
authors.forename: Monika
authors.initials: M
authors.lastname: Puzianowska-Kuznicka
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Krystyniak
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Madej
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
authors.forename: Janusz
authors.initials: J
authors.lastname: Nauman
mesh_terms: D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism; D012016:Reference Values; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta