Restoration of thyroid hormone receptor beta signaling re-programs anaplastic thyroid cancer cells
Conference Year
January 2019
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 (TRb) is correlated with aggressive disease and decreased survival in other human cancer types, including breast cancer, hepatocellular carcinoma, and melanoma, suggesting a tumor suppressor role1-3. Decreased TRb expression is observed in patients with ATC via tissue microarray4 and in representative ATC cell lines5. To test the hypothesis that rescue of TRb can restore a tumor suppressor program and a more differentiated phenotype in ATC cells, we re-introduced constitutive TRb expression in the SW1736 ATC cell line by stable lentiviral transduction. Proliferation assays reveal that SW1736 cells expressing TRb 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 TRb and the empty vector control cells to determine the potential mechanisms underlying this observation. Establishment of TRb 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 TGFb signalling. Upstream regulators of this transcriptional response included many epigenetic regulators, most notably BRG1, KDM5B, and BRD4. This suggests that restoration of TRb 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 TRb 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 TRb 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.
- Martinez-Iglesias, O. et al. Cancer Res 69, 501-509, (2009).
- Aranda, A. et al. Trends in endocrinology and metabolism: TEM 20, 318-324, (2009).
- Suzuki, H., et al. Thyroid 12, 963-969, (2002).
- Landa, I. et al. J Clin Invest 126, 1052-1066, (2016).
- Carr, F. E. et al. Endocrinology 157, 3278-3292, (2016).
Primary Faculty Mentor Name
Frances Carr
Status
Graduate
Student College
Larner College of Medicine
Second Student College
Graduate College
Program/Major
Cellular, Molecular and Biomedical Sciences
Primary Research Category
Biological Sciences
Secondary Research Category
Health Sciences
Restoration of thyroid hormone receptor beta signaling re-programs anaplastic thyroid cancer cells
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 (TRb) is correlated with aggressive disease and decreased survival in other human cancer types, including breast cancer, hepatocellular carcinoma, and melanoma, suggesting a tumor suppressor role1-3. Decreased TRb expression is observed in patients with ATC via tissue microarray4 and in representative ATC cell lines5. To test the hypothesis that rescue of TRb can restore a tumor suppressor program and a more differentiated phenotype in ATC cells, we re-introduced constitutive TRb expression in the SW1736 ATC cell line by stable lentiviral transduction. Proliferation assays reveal that SW1736 cells expressing TRb 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 TRb and the empty vector control cells to determine the potential mechanisms underlying this observation. Establishment of TRb 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 TGFb signalling. Upstream regulators of this transcriptional response included many epigenetic regulators, most notably BRG1, KDM5B, and BRD4. This suggests that restoration of TRb 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 TRb 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 TRb 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.
- Martinez-Iglesias, O. et al. Cancer Res 69, 501-509, (2009).
- Aranda, A. et al. Trends in endocrinology and metabolism: TEM 20, 318-324, (2009).
- Suzuki, H., et al. Thyroid 12, 963-969, (2002).
- Landa, I. et al. J Clin Invest 126, 1052-1066, (2016).
- Carr, F. E. et al. Endocrinology 157, 3278-3292, (2016).