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Other Original Articles |
Department of Endocrinology, Medical Research Center, Polish Academy of Sciences (M.P.-K., A.K., A.M., J.N.), and Department of Biochemistry, Medical Center of Postgraduate Education (M.P.-K.), 02-097 Warsaw, Poland; and Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health (S.-Y.C.), Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Dr. Monika Puzianowska-Kuznicka, Department of Endocrinology, Medical Research Center, 1a Banacha Street, 02-097 Warsaw, Poland. E-mail: . monika{at}amwaw.edu.pl
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 4045% of cases. We found that the mean expression levels of TRß mRNA and TR
mRNA were significantly lower, whereas the protein levels of TRß1 and TR
1 were higher in cancer tissues than in healthy thyroid. Sequencing of TRß1 and TR
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 TRß1 or TR
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.
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