Thyroid Hormone Receptor Beta as Tumor Suppressor: Untapped Potential in Treatment and Diagnostics in Solid Tumors

SIMPLE SUMMARY: Dysregulation of the thyroid hormone receptor beta (TRβ) is characteristic of many solid and endocrine-related tumors. Despite a recognized role as a tumor suppressor, the mechanisms by which TRβ regulates tumor growth are not yet clear. As a transcription factor that responds to changes in thyroid hormone levels, TRβ plays a key role in regulating many cell signaling nodes that are important for maintenance of normal cell identity and tumor progression. This review will address the need for a deeper understanding of TRβ tumor suppressor mechanisms to inform the development of more effective thyroid cancer diagnostics and therapies. ABSTRACT: There is compelling evidence that the nuclear receptor TRβ, a member of the thyroid hormone receptor (TR) family, is a tumor suppressor in thyroid, breast, and other solid tumors. Cell-based and animal studies reveal that the liganded TRβ induces apoptosis, reduces an aggressive phenotype, decreases stem cell populations, and slows tumor growth through modulation of a complex interplay of transcriptional networks. TRβ-driven tumor suppressive transcriptomic signatures include repression of known drivers of proliferation such as PI3K/Akt pathway, activation of novel signaling such as JAK1/STAT1, and metabolic reprogramming in both thyroid and breast cancers. The presence of TRβ is also correlated with a positive prognosis and response to therapeutics in BRCA(+) and triple-negative breast cancers, respectively. Ligand activation of TRβ enhances sensitivity to chemotherapeutics. TRβ co-regulators and bromodomain-containing chromatin remodeling proteins are emergent therapeutic targets. This review considers TRβ as a potential biomolecular diagnostic and therapeutic target.