Presentation Title
Characterization of the Gene Expression Program of a Mutant Thyroid Hormone Receptor in Anaplastic Thyroid Cancer
Abstract
Thyroid cancer is the most commonly diagnosed endocrine malignancy. Although survival rates for the majority of thyroid cancer subtypes are high compared to other cancers, the de-differentiated anaplastic thyroid cancer (ATC) is particularly aggressive, with a median survival time of less than 6 months. Intriguingly, thyroid hormone receptor beta (TRβ) has been demonstrated to repress tumor growth in thyroid cancer models, but the mechanism is not well established. Additionally, phosphorylation of a tyrosine residue (Y406) is critical for the tumor suppressive phenotype of TRβ; mutation of this residue ablates TRβ-mediated tumor suppression. We hypothesized that the signaling mediated by wild type, but not Y406 TRβ defines the critical pathways for tumor suppression. We restored WT or Y406F TRβ expression by lentiviral transduction in an authenticated ATC cell line, SW1736. WT TRβ decreased cell proliferation, an effect amplified by T3. Y406F did not significantly reduce ATC cell proliferation and addition of T3 did not restore the antiproliferative effect implicating differential signaling. As we have previously identified TRb suppression of the oncogene RUNX2 in thyroid cells, we determined the impact of Y406F TRβ on this signaling pathway. While Y406F TRβ reduced RUNX2 expression, the effect was less pronounced than noted with WT. Of importance, we previously demonstrated that the chromatin ATPase BRG1 cooperates with TRβ to reduce RUNX2 levels. Mutation of TRb at Y406 eliminated this synergy. Finally, we determined the ligand-dependent and independent transcriptomes of WT and Y406F TRβ by RNA-sequencing. Critically, WT and Y406F TRβ both responded to T3 treatment, but exhibit different transcriptional profiles. These results define the TRβ transcriptome in aggressive thyroid cancer cells and reveal novel signaling in ATC.
Primary Faculty Mentor Name
Frances Carr
Status
Graduate
Student College
Graduate College
Program/Major
Cellular, Molecular and Biomedical Sciences
Primary Research Category
Biological Sciences
Characterization of the Gene Expression Program of a Mutant Thyroid Hormone Receptor in Anaplastic Thyroid Cancer
Thyroid cancer is the most commonly diagnosed endocrine malignancy. Although survival rates for the majority of thyroid cancer subtypes are high compared to other cancers, the de-differentiated anaplastic thyroid cancer (ATC) is particularly aggressive, with a median survival time of less than 6 months. Intriguingly, thyroid hormone receptor beta (TRβ) has been demonstrated to repress tumor growth in thyroid cancer models, but the mechanism is not well established. Additionally, phosphorylation of a tyrosine residue (Y406) is critical for the tumor suppressive phenotype of TRβ; mutation of this residue ablates TRβ-mediated tumor suppression. We hypothesized that the signaling mediated by wild type, but not Y406 TRβ defines the critical pathways for tumor suppression. We restored WT or Y406F TRβ expression by lentiviral transduction in an authenticated ATC cell line, SW1736. WT TRβ decreased cell proliferation, an effect amplified by T3. Y406F did not significantly reduce ATC cell proliferation and addition of T3 did not restore the antiproliferative effect implicating differential signaling. As we have previously identified TRb suppression of the oncogene RUNX2 in thyroid cells, we determined the impact of Y406F TRβ on this signaling pathway. While Y406F TRβ reduced RUNX2 expression, the effect was less pronounced than noted with WT. Of importance, we previously demonstrated that the chromatin ATPase BRG1 cooperates with TRβ to reduce RUNX2 levels. Mutation of TRb at Y406 eliminated this synergy. Finally, we determined the ligand-dependent and independent transcriptomes of WT and Y406F TRβ by RNA-sequencing. Critically, WT and Y406F TRβ both responded to T3 treatment, but exhibit different transcriptional profiles. These results define the TRβ transcriptome in aggressive thyroid cancer cells and reveal novel signaling in ATC.