Thyroid Hormone Receptor Beta Induces a Tumor Suppressive Program in Anaplastic Thyroid Cancer

The thyroid hormone receptor beta (TRβ), a key regulator of cellular growth and differentiation, is frequently dysregulated in cancers. Diminished expression of TRb is noted in thyroid, breast, and other solid tumors and is correlated with more aggressive disease. Restoration of TRb levels decreased tumor growth supporting the concept that TRb could function as a tumor suppressor. Yet, the TRb tumor suppression transcriptome is not well delineated and the impact of TRb is unknown in aggressive anaplastic thyroid cancer (ATC). Here, we establish that restoration of TRb expression in the human ATC cell line SW1736 (SW-TRβ) reduces the aggressive phenotype, decreases cancer stem-cell populations and induces cell death in a T3-dependent manner. Transcriptomic analysis of SW-TRβ cells via RNA-sequencing revealed distinctive expression patterns induced by ligand-bound TRβ and revealed novel molecular signaling pathways. Of note, liganded TRβ repressed multiple nodes in the PI3K/AKT pathway, induced expression of thyroid differentiation markers, and promoted pro-apoptotic pathways. Our results further revealed the JAK1-STAT1 pathway as a novel, T3-mediated, anti-tumorigenic pathway that can be activated in additional ATC lines. These findings elucidate a TRb-driven tumor suppression transcriptomic signature, highlight unexplored therapeutic options for ATC, and support TRb activation as a promising therapeutic option in cancers.