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

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.

Subcellular Distribution of Thyroid Hormone Receptor Beta in Ovarian Cancer

“…Whether the correlation is caused solely by chance, or whether there is a tumor-biologic reason that links TR beta with parameters related to disease aggressiveness (e.g., advanced FIGO stage, high grade, histologic subtype), remains to be elucidated. Finally, the biologic meaning of TR beta and its prognostic role might also depend on the cancer entity studied, as several analyses performed in breast, thyroid and gastrointestinal cancers propose TR beta to predict favorable prognosis [ 19 , 20 , 25 ].…”

Alterations of DNA methylation and expression of genes related to thyroid hormone metabolism in colon epithelium of obese patients

“…According to several lines of evidence, pro-cancerous effects of THs are exerted via either TRα or integrin avβ3 by promoting angiogenesis, proliferation, apoptosis suppression, evasion from immune surveillance, and metabolic reprogramming [ 9 ]. Convincing evidence suggests that TRβ is a tumor suppressor in several types of cancer, including thyroid, breast, colorectal and other solid tumors [ 10 ]. Downregulation of TRβ is the characteristic of many cancers [ 10 ].…”

Inhibition of Glycogen Metabolism Induces Reactive Oxygen Species-Dependent Apoptosis in Anaplastic Thyroid Cancer

“…While glycogen represents a promising metabolic target in cancer, glycogen stores have only been reported in normal canine and bovine thyroids and the very rare clear cell thyroid carcinoma [23][24][25] . We recently hypothesized that thyroid cancer may utilize glycogen metabolism for tumor progression based on our own RNAsequencing data and publicly available databases 26 . Therefore, our goal was to investigate the presence and role of glycogen in human thyroid tissues and cell lines and to determine the therapeutic potential of inhibiting glycogen metabolism.…”