TRß Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice.

Thyroid hormone receptor beta (TRß) is a recognized tumor suppressor in numerous solid cancers. The molecular signaling of TRß has been elucidated in several cancer types through re-expression models. Remarkably, the potential impact of selective activation of endogenous TRß on tumor progression remains largely unexplored. We used cell-based and in vivo assays to evaluate the effects of the TRß agonist sobetirome (GC-1) on a particularly aggressive and dedifferentiated cancer, anaplastic thyroid cancer (ATC). Here we report that GC-1 reduced the tumorigenic phenotype, decreased cancer stem-like cell populations, and induced redifferentiation of the ATC cell lines with different mutational backgrounds. Of note, this selective activation of TRß amplified the effects of therapeutic agents in blunting the aggressive cell phenotype and stem cell growth. In xenograft assays, GC-1 alone inhibited tumor growth and was as effective as the kinase inhibitor, sorafenib. These results indicate that selective activation of TRß not only induces a tumor suppression program de novo but enhances the effectiveness of anticancer agents, revealing potential novel combination therapies for ATC and other aggressive solid tumors.

Dasatinib and Trametinib Promote Anti-Tumor Metabolic Activity.

Thyroid cancer is the most common endocrine neoplasm, and despite its overall high survival rate, patients with metastatic disease or tumors that resist radioactive iodine experience a significantly worse prognosis. Helping these patients requires a better understanding of how therapeutics alter cellular function. Here, we describe the change in metabolite profiles after treating thyroid cancer cells with the kinase inhibitors dasatinib and trametinib. We reveal alterations to glycolysis, the TCA cycle, and amino acid levels. We also highlight how these drugs promote short-term accumulation of the tumor-suppressive metabolite 2-oxoglutarate, and demonstrate that it reduces the viability of thyroid cancer cells in vitro. These results show that kinase inhibition profoundly alters the metabolome of cancer cells and highlight the need to better understand how therapeutics reprogram metabolic processes, and ultimately, cancer cell behavior.

Common tumor-suppressive signaling of thyroid hormone receptor beta in breast and thyroid cancer cells.

The thyroid hormone receptor beta (TRß) is a tumor suppressor in multiple types of solid tumors, most prominently in breast and thyroid cancer. An increased understanding of the molecular mechanisms by which TRß abrogates tumorigenesis will aid in understanding the core tumor-suppressive functions of TRß. Here, we restored TRß expression in the MDA-MB-468 basal-like breast cancer cell line and perform RNA-sequencing to determine the TRß-mediated changes in gene expression and associated signaling pathways. The TRß expressing MDA-MB-468 cells exhibit a more epithelial character as determined by principle component analysis-based iterative PAM50 subtyping score and through reduced expression of mesenchymal cytokeratins. The epithelial to mesenchymal transition pathway is also significantly reduced. The MDA-MB-468 data set was further compared with RNA sequencing results from TRß expressing thyroid cancer cell line SW1736 to determine which genes are TRß correspondingly regulated across both cell types. Several pathways including lipid metabolism and chromatin remodeling processes were observed to be altered in the shared gene set. These data provide novel insights into the molecular mechanisms by which TRß suppresses breast tumorigenesis.

Thyroid Hormone Receptor Beta Inhibits PI3K-Akt-mTOR Signaling Axis in Anaplastic Thyroid Cancer via Genomic Mechanisms.

Thyroid cancer is the most common endocrine malignancy, and the global incidence has increased rapidly over the past few decades. Anaplastic thyroid cancer (ATC) is highly aggressive, dedifferentiated, and patients have a median survival of fewer than 6 months. Oncogenic alterations in ATC include aberrant phosphoinositide 3 kinase (PI3K) signaling through receptor tyrosine kinase (RTK) amplification, loss of phosphoinositide phosphatase expression and function, and protein kinase B (Akt) amplification. Furthermore, the loss of expression of the tumor suppressor thyroid hormone receptor beta (TRß) is strongly associated with ATC. TRß is known to suppress PI3K in follicular thyroid cancer and breast cancer by binding to the PI3K regulatory subunit p85α. However, the role of TRß in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TRß indeed suppresses PI3K signaling in ATC cell lines through unreported genomic mechanisms, including a decrease in RTK expression and an increase in phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TRß in ATC cell lines enables an increase in the efficacy of the competitive PI3K inhibitors LY294002 and buparlisib on cell viability, migration, and suppression of PI3K signaling. These findings not only uncover additional tumor suppressor mechanisms of TRß but shed light on the implication of TRß status and activation on inhibitor efficacy in ATC tumors.

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

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

The Thyroid Hormone Receptor-RUNX2 Axis: A Novel Tumor Suppressive Pathway in Breast Cancer.

Metastatic breast cancer is refractory to conventional therapies and is an end-stage disease. RUNX2 is a transcription factor that becomes oncogenic when aberrantly expressed in multiple tumor types, including breast cancer, supporting tumor progression and metastases. Our previous work demonstrated that the thyroid hormone receptor beta (TRß) inhibits RUNX2 expression and tumorigenic characteristics in thyroid cells. As TRß is a tumor suppressor, we investigated the compelling question whether TRß also regulates RUNX2 in breast cancer. The Cancer Genome Atlas indicates that TRß expression is decreased in the most aggressive basal-like subtype of breast cancer. We established that modulated levels of TRß results in corresponding changes in the high levels of RUNX2 expression in metastatic, basal-like breast cells. The MDA-MB-231 triple-negative breast cancer cell line exhibits low expression of TRß and high levels of RUNX2. Increased expression of TRß decreased RUNX2 levels. The thyroid hormone-mediated suppression of RUNX2 is TRß specific as TRα overexpression failed to alter RUNX2 expression. Consistent with these findings, knockdown of TRß in non-tumor MCF10A mammary epithelial-like cells results in an increase in RUNX2 and RUNX2 target genes. Mechanistically, TRß directly interacts with the proximal promoter of RUNX2 through a thyroid hormone response element to reduce promoter activity. The TRß suppression of the oncogene RUNX2 is a signaling pathway shared by thyroid and breast cancers. Our findings provide a novel mechanism for TRß-mediated tumor suppression in breast cancers. This pathway may be common to many solid tumors and impact treatment for metastatic cancers.

A Linkage Between Thyroid and Breast Cancer: A Common Etiology?

Breast and thyroid cancers are two malignancies with highest incidence in women. These cancers often occur metachronously. Women with thyroid cancer are at increased risk for subsequent breast cancer; women with breast cancer have an increased incidence of later development of thyroid cancer, suggesting a common etiology. This bidirectional relationship is reported worldwide; however, the underlying reasons for this co-occurrence are unknown. In this review, we summarize the current epidemiologic evidence and putative mechanisms of these metachronous or synchronous cancers. Key potential causative factors are chemotherapy and radiotherapy of the primary tumor, genetic variants linking the two diseases, hormonal signaling both from the thyroid gland and from estrogens, and lifestyle and environmental factors. There is a critical need for additional epidemiologic studies focused on gender and regional incidence together with molecular investigations on common tumorigenic pathways in these endocrine cancers. Understanding the putative mechanisms will aid in the diagnosis and clinical management of both diseases.

Thyroid Hormone Receptor ß Suppression of RUNX2 Is Mediated by Brahma-Related Gene 1-Dependent Chromatin Remodeling.

Thyroid hormone receptor ß (TRß) suppresses tumor growth through regulation of gene expression, yet the associated TRß-mediated changes in chromatin assembly are not known. The chromatin ATPase brahma-related gene 1 (BRG1; SMARCA4), a key component of chromatin-remodeling complexes, is altered in many cancers, but its role in thyroid tumorigenesis and TRß-mediated gene expression is unknown. We previously identified the oncogene runt-related transcription factor 2 (RUNX2) as a repressive target of TRß. Here, we report differential expression of BRG1 in nonmalignant and malignant thyroid cells concordant with TRß. BRG1 and TRß have similar nuclear distribution patterns and significant colocalization. BRG1 interacts with TRß, and together, they are part of the regulatory complex at the RUNX2 promoter. Loss of BRG1 increases RUNX2 levels, whereas reintroduction of TRß and BRG1 synergistically decreases RUNX2 expression. RUNX2 promoter accessibility corresponded to RUNX2 expression levels. Inhibition of BRG1 activity increased accessibility of the RUNX2 promoter and corresponding expression. Our results reveal a mechanism of TRß repression of oncogenic gene expression: TRß recruitment of BRG1 induces chromatin compaction and diminishes RUNX2 expression. Therefore, BRG1-mediated chromatin remodeling may be obligatory for TRß transcriptional repression and tumor suppressor function in thyroid tumorigenesis.