SAT-571 Restoration of Thyroid Hormone Receptor Beta Signaling Reprograms Anaplastic Thyroid Cancer Cells

Abstract

Anaplastic thyroid cancer (ATC) is among the most lethal human cancers, with an average survival time of six months. These tumors are characterized by rapid local extension, resistance to radioactive iodine therapy and mainstream chemotherapy, and distant metastasis. There are very limited treatment options for this aggressive form of thyroid cancer, highlighting a need for a deeper understanding of its mechanisms for development of new targeted therapies. Loss of expression of the thyroid hormone receptor beta (TRβ) is correlated with aggressive disease and decreased survival in other human cancer types, including breast cancer, hepatocellular carcinoma, and melanoma, suggesting a tumor suppressor role 1-3 . Decreased TRβ expression is observed in patients with ATC via tissue microarray 4 and in representative ATC cell lines 5 . To test the hypothesis that rescue of TRβ can restore a tumor suppressor program and a more differentiated phenotype in ATC cells, we re-introduced constitutive TRβ expression in the SW1736 ATC cell line by stable lentiviral transduction. Proliferation assays reveal that SW1736 cells expressing TRβ have a 30% decrease in proliferation rate compared to empty vector control cells. This prompted us to examine the differences in the transcriptome between our SW1736 cells expressing TRβ and the empty vector control cells to determine the potential mechanisms underlying this observation. Establishment of TRβ expression restored a transcriptional response to thyroid hormone treatment, in concordance with our proliferation studies. Upon transcript quantitation and downstream pathway analysis, we observed changes in several pathways that are well known to influence thyroid cancer growth, including mTOR, PTEN, and TGFβ signalling. Upstream regulators of this transcriptional response included many epigenetic regulators, most notably BRG1, KDM5B, and BRD4. This suggests that restoration of TRβ signalling results in a ligand-dependent chromatin remodeling response to facilitate the gene expression changes we observed. In addition, we measured changes in markers of thyroid differentiation by qPCR and found that TRβ expression and treatment with thyroid hormone increased expression of several key genes including TPO, DIO1, and NIS. In summary, our data support a role for TRβ as a tumor suppressor and mediator of thyroid differentiation in thyroid cells. Importantly, our analyses will direct further investigation into targets and pathways that can be exploited as therapeutic strategies in ATC. 1. Martinez-Iglesias, O. et al. Cancer Res 69 , 501-509, (2009). 2. Aranda, A. et al. Trends in endocrinology and metabolism: TEM 20 , 318-324, (2009). 3. Suzuki, H., et al. Thyroid 12 , 963-969, (2002). 4. Landa, I. et al. J Clin Invest 126 , 1052-1066,...

Suppression of Calcium Entry Modulates the Expression of TRβ1 and Runx2 in Thyroid Cancer Cells, Two Transcription Factors That Regulate Invasion, Proliferation and Thyroid-Specific Protein Levels

“…The importance of both TRβ1 and Runx2 has been investigated in several forms of cancer, including breast and thyroid cancer. In these cancers, TRβ1 has been considered to function as a tumor suppressor, and Runx2 as an oncogene [ 39 , 41 ]. Several investigations have shown that overexpression of TRβ1 reduces tumor growth, invasion, and metastasis in thyroid cancer [ 42 , 43 ].…”