scholarly journals Thyroid hormone receptor beta inhibits the PI3K-Akt-mTOR signaling axis in anaplastic thyroid cancer cell lines via genomic mechanisms

2021 ◽  
Author(s):  
Cole D Davidson ◽  
Eric L Bolf ◽  
Noelle E Gillis ◽  
Lauren M Cozzens ◽  
Jennifer A Tomczak ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Anaplastic Thyroid Cancer ◽  
Regulatory Subunit ◽  
Pi3k Signaling ◽  
Receptor Beta

Abstract 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 six months. Oncogenic alterations in ATC include aberrant PI3K signaling through receptor tyrosine kinase (RTK) amplification, loss of phosphoinositide phosphatase expression and function, and Akt amplification. Furthermore, the loss of expression of the tumor suppressor thyroid hormone receptor beta (TRβ) is strongly associated with ATC. TRβ is known to suppress PI3K in follicular thyroid cancer and breast cancer by binding to the PI3K regulatory subunit p85⍺. However, the role of TRβ in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TRβ indeed suppresses PI3K signaling in ATC cell lines through unreported genomic mechanisms including a decrease in RTK expression and increase in phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TRβ 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 TRβ but shed light into the implication of TRβ status and activation on inhibitor efficacy in ATC tumors.

scholarly journals Thyroid hormone receptor beta inhibits the PI3K-Akt-mTOR signaling axis in anaplastic thyroid cancer via genomic mechanisms

2020 ◽  
Author(s):  
Cole D. Davidson ◽  
Eric L. Bolf ◽  
Noelle E. Gillis ◽  
Lauren M. Cozzens ◽  
Jennifer A. Tomczak ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Tumor Suppressor ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Anaplastic Thyroid Cancer ◽  
Regulatory Subunit ◽  
Pi3k Signaling ◽  
Phosphoinositide Phosphatase ◽  
Receptor Beta

AbstractThyroid 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 six months. Oncogenic alterations in ATC include aberrant PI3K signaling through receptor tyrosine kinase (RTK) amplification, loss of phosphoinositide phosphatase expression and function, and Akt amplification. Furthermore, the loss of expression of the tumor suppressor thyroid hormone receptor beta (TRβ) is strongly associated with ATC. TRβ is known to suppress PI3K in follicular thyroid cancer and breast cancer by binding to the PI3K regulatory subunit p85α. However, the role of TRβ in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TRβ indeed suppresses PI3K signaling in ATC through unreported genomic mechanisms including a decrease in RTK expression and increase in phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TRβ in ATC 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 TRβ but shed light into the implication of TRβ status and activation on inhibitor efficacy in ATC tumors.Abstract FigureGraphical abstract

scholarly journals A Thyroid Hormone Receptor Beta Specific Agonist Suppresses Anaplastic Thyroid Cancer Cell Phenotype and Increases Efficacy of Therapeutic Agents

2021 ◽  
Author(s):  
Noelle E Gillis ◽  
Cole D Davidson ◽  
Lauren M Cozzens ◽  
Emily R Wilson ◽  
Eric L Bolf ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Anaplastic Thyroid Cancer ◽  
Therapeutic Agents ◽  
Selective Activation ◽  
Aggressive Phenotype ◽  
Receptor Beta

Background: Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers, with an average survival time of six months after diagnosis. These aggressive tumors have very limited treatment options highlighting a need for a deeper understanding of its mechanisms for development of more effective therapies. We have previously shown that the liganded thyroid hormone receptor beta (TRβ) can function as a tumor suppressor and induce re-differentiation in ATC cells. We therefore tested the hypothesis that selective activation of TRβ with sobetirome (GC-1) could reduce the tumorigenic phenotypes of ATC cell lines and improve the efficacy of clinically relevant therapeutics. Methods: We used a panel of four ATC cell lines with variable genetic backgrounds to assess the ability of GC-1 to reduce the aggressive phenotype. The effects of GC-1 alone or in combination with buparlisib, alpelisib, sorafenib, and palbociclib on cell growth, viability, and migration were determined and compared with the gene expression levels of selected markers. The impact of these treatments on the cancer stem cell population was assessed by tumorsphere assay. Thyroid differentiation markers were measured by gene analysis, and sodium iodide symporter (NIS) protein level and function were determined. Results: Our results show that GC-1 alone can decrease cell viability, growth, and slow cell migration in all four ATC cell lines. In addition, GC-1 is able to further block each of these phenotypes when combined with buparlisib, alpelisib, sorafenib, or palbociclib. GC-1 alone blocks thyrosphere outgrowth in all cell lines and increases the efficacy of each of the therapeutic agents tested. GC-1 increased NIS transcript and protein levels to allow for increased iodide uptake in ATC cells. Conclusion: Activation of TRβ with selective agonist sobetirome (GC-1) reduces the aggressive phenotype and induced re-differentiation in ATC cells and increases the efficacy of therapeutic agents that are currently used in the treatment of ATC. These results indicate that selective activation of TRβ not only induces a tumor suppression program de novo but enhances the effectiveness of anti-cancer agents.

scholarly journals SAT-571 Restoration of Thyroid Hormone Receptor Beta Signaling Reprograms Anaplastic Thyroid Cancer Cells

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Noelle Gillis ◽  
Eric Bolf ◽  
Cole Davidson ◽  
Jennifer Tomczak ◽  
Seth Frietze ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Cancer Cells ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Anaplastic Thyroid Cancer ◽  
Thyroid Cancer Cells ◽  
Receptor Beta

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

2020 ◽  
Vol 18 (10) ◽  
pp. 1443-1452 ◽  
Author(s):  
Eric L. Bolf ◽  
Noelle E. Gillis ◽  
Cole D. Davidson ◽  
Princess D. Rodriguez ◽  
Lauren Cozzens ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Anaplastic Thyroid Cancer ◽  
Receptor Beta

scholarly journals Thyroid hormone receptor β mutations in the ‘hot-spot region’ are rare events in thyroid carcinomas

2007 ◽  
Vol 192 (1) ◽  
pp. 83-86 ◽  
Author(s):  
Ana Sofia Rocha ◽  
Ricardo Marques ◽  
Inês Bento ◽  
Ricardo Soares ◽  
João Magalhães ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Transgenic Mice ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Hot Spot ◽  
Direct Sequencing ◽  
Human Thyroid ◽  
Thyroid Hormone Receptor Β

Thyroid cancer constitutes the most frequent endocrine neoplasia. Targeted expression of rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) and V600E V-raf murine sarcoma viral oncogene homolog B1 (BRAF) to the thyroid glands of transgenic mice results in tumours similar to those of human PTC, providing evidence for the involvement of these oncogenes in PTC. Kato et al. developed a mouse model that mimics the full spectrum of the human follicular form of thyroid cancer (FTC). FTC rapidly develops in these mice through introduction of the thyroid hormone receptor β (THRB)PV mutant on the background of the inactivated THRB wt locus. Our aim was to verify if, in the context of human follicular thyroid carcinogenesis, THRB acted as a tumour suppressor gene. We screened for mutations of the THRB gene in the hot-spot region, spanning exons 7–10, in 51 thyroid tumours and six thyroid cancer cell lines by PCR and direct sequencing. We did not find mutations in any of the tumours or cell lines analysed. Our findings suggest that, in contrast to the findings on the THRB-mutant transgenic mice, THRB gene mutations are not a relevant mechanism for human thyroid carcinogenesis.

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

2021 ◽  
Author(s):  
Eric L. Bolf ◽  
Noelle E. Gillis ◽  
Cole D. Davidson ◽  
Lauren M. Cozzens ◽  
Sophie Kogut ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Cancer Cells ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Thyroid Cancer Cells ◽  
Receptor Beta

scholarly journals Thyroid Hormone Receptor-β (TRβ) Mediates Runt-Related Transcription Factor 2 (Runx2) Expression in Thyroid Cancer Cells: A Novel Signaling Pathway in Thyroid Cancer

Endocrinology ◽  
2016 ◽  
Vol 157 (8) ◽  
pp. 3278-3292 ◽  
Author(s):  
Frances E. Carr ◽  
Phillip W. L. Tai ◽  
Michael S. Barnum ◽  
Noelle E. Gillis ◽  
Katherine G. Evans ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Tumor Suppressor ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Hormone Response ◽  
Thyroid Cells ◽  
Runx2 Expression ◽  
Related Transcription Factor

Dysregulation of the thyroid hormone receptor (TR)β is common in human cancers. Restoration of functional TRβ delays tumor progression in models of thyroid and breast cancers implicating TRβ as a tumor suppressor. Conversely, aberrant expression of the runt-related transcription factor 2 (Runx2) is established in the progression and metastasis of thyroid, breast, and other cancers. Silencing of Runx2 diminishes tumor invasive characteristics. With TRβ as a tumor suppressor and Runx2 as a tumor promoter, a compelling question is whether there is a functional relationship between these regulatory factors in thyroid tumorigenesis. Here, we demonstrated that these proteins are reciprocally expressed in normal and malignant thyroid cells; TRβ is high in normal cells, and Runx2 is high in malignant cells. T3 induced a time- and concentration-dependent decrease in Runx2 expression. Silencing of TRβ by small interfering RNA knockdown resulted in a corresponding increase in Runx2 and Runx2-regulated genes, indicating that TRβ levels directly impact Runx2 expression and associated epithelial to mesenchymal transition molecules. TRβ specifically bound to 3 putative thyroid hormone-response element motifs within the Runx2-P1 promoter (−105/+133) as detected by EMSA and chromatin immunoprecipitation. TRβ suppressed Runx2 transcriptional activities, thus confirming TRβ regulation of Runx2 at functional thyroid hormone-response elements. Significantly, these findings indicate that a ratio of the tumor-suppressor TRβ and tumor-promoting Runx2 may reflect tumor aggression and serve as biomarkers in biopsy tissues. The discovery of this TRβ-Runx2 signaling supports the emerging role of TRβ as a tumor suppressor and reveals a novel pathway for intervention.

scholarly journals OR21-03 Determining Novel Therapeutic Targets Using an in Vitro Model of TRb Tumor Suppression in Anaplastic Thyroid Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Noelle E Gillis ◽  
Eric L Bolf ◽  
Cole Davidson ◽  
Lauren Cozzens ◽  
Jennifer Tomczak ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Therapeutic Targets ◽  
Anaplastic Thyroid Cancer ◽  
Hormone Treatment ◽  
Novel Therapeutic

Abstract Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers, with an average survival time of six months after diagnosis. These aggressive tumors are characterized by rapid local extension, distant metastasis, and resistance to radioactive iodine therapy and mainstream chemotherapy. There are very limited treatment options for this aggressive form of thyroid cancer, highlighting a need for a deeper understanding of its mechanisms for development of more effective therapies. Loss of expression of the thyroid hormone receptor beta (TRβ) via epigenetic silencing is common amongst solid tumors, including ATC. Despite its recognized role as a tumor suppressor, the mechanisms underlying TRβ tumor suppressor activity remain uncharacterized. We previously created a stable ATC cell line with constitutive re-expression of TRβ (SW-TRβ). These stable cells exhibit a slower baseline growth rate than both the corresponding parental cell line (SW1736) and the stable empty vector control cell line (SW-EV). Since the effects of thyroid hormone treatment on the growth of cancer cells remain unclear, we investigated changes in growth rates of these cells in response to hormone treatment (triiodothyronine (T3) 10-8M). While T3 had no effect on SW-EV cells, the addition of hormone significantly slowed the growth of the SW-TRβ cells after two days. With longer exposure to T3 (five days), the SW-TRβ cells exhibited an apoptotic phenotype. We confirmed that the observed cell death was due to induction of apoptosis by assessing caspase 3 cleavage by immunoblot. The parental SW1736 cell line harbors a deleterious p53 truncating mutation, which is maintained in our stable cell lines. Therefore, we hypothesize that this T3-induced apoptosis is occurring through an alternate, p53-independent, signaling pathway. This prompted us to examine RNA-seq data obtained from these cell lines under similar conditions to identify potential regulators of this response. Interestingly, pathway analysis revealed decreased CDK4/6-mediated cell cycle progression and activation of JAK1/STAT1 signaling upon T3 treatment. These are novel mechanisms by which activation of T3-TRβ signaling can slow tumor growth and promote apoptosis in p53-deficient cancer cells. Furthermore, these pathways represent novel therapeutic targets specifically for ATC with potential high impact clinical applications.

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