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Thyroid Hormone Receptors as Tumor Suppressors in Cancer
Abstract
Accumulated research has revealed the multifaceted roles of thyroid hormone receptors (TRs) as potent tumor suppressors across various cancer types. This review explores the intricate mechanisms underlying TR-mediated tumor suppression, drawing insights from preclinical mouse models and cancer biology. This review examines the tumor-suppressive functions of TRs, particularly TRβ, in various cancers using preclinical models, revealing their ability to inhibit tumor initiation, progression, and metastasis. Molecular mechanisms underlying TR-mediated tumor suppression are discussed, including interactions with oncogenic signaling pathways like PI3K-AKT, JAK-STAT, and transforming growth factor β. Additionally, this paper examines TRs’ effect on cancer stem cell activity and differentiation, showcasing their modulation of key cellular processes associated with tumor progression and therapeutic resistance. Insights from preclinical studies underscore the therapeutic potential of targeting TRs to impede cancer stemness and promote cancer cell differentiation, paving the way for precision medicine in cancer treatment and emphasizing the potential of TR-targeted therapies as promising approaches for treating cancers and improving patient outcomes.
Thyroid hormone (3,5,3′-triiodothyronine, T3) plays vital roles in regulating metabolism (1, 2). It influences the body's energy expenditure and maintains overall metabolic balance. It is crucial for normal growth and development, particularly in the brain and skeletal system. T3 also affects cardiovascular function by regulating heart rate, blood pressure, and vascular tone. Additionally, it helps in maintaining body temperature, reproductive function, and mood regulation, highlighting its diverse physiological effects throughout the body. Overall, T3 is essential for the proper functioning of virtually every organ system and process in the body (3-7).
Once complementary DNA of thyroid hormone receptors (TRs) was cloned (8-11), it became evident that the binding of T3 to its receptors is critical for coordinating the biological effects of T3 across the body. These receptors are in the nucleus of target cells and act as ligand-activated transcription factors. TRs, part of the ligand-dependent transcription factor superfamily (12), are encoded by THRA and THRB genes on chromosomes 3 and 17, respectively. Alternative splicing produces 3 major receptor proteins (β1, β2, and α1). The expression of TR isoforms varies across tissues and is subject to developmental regulation. TRα1 is mainly found in the heart conduction system, bone, and brain, while TRβ1 is more prevalent in the liver, kidney, and thyroid (13, 14). TRβ2 is limited to the pituitary gland, hypothalamus, retina, and inner ear (13).
When T3 binds to TRs, the interaction of T3 with TRs triggers conformational changes in the receptor, enabling it to bind to specific DNA sequences called thyroid hormone response elements (TREs) within the promoters of target genes (15). This binding initiates or enhances the transcription of these target genes, leading to changes in gene expression and ultimately influencing cellular function and metabolism. Additionally, TRs can exert diverse effects on gene transcription, depending on the presence of coregulator proteins (16), which interact with TRs to modulate their transcriptional activity either positively or negatively. Coregulators can influence the recruitment of RNA polymerase and other transcriptional machinery, ultimately shaping the cellular response to T3. Overall, the interaction between T3 and its receptors is tightly regulated and crucial for mediating the diverse physiological effects of T3 on metabolism, growth, development, and numerous other cellular processes throughout the body. Any disruption in this finely tuned mechanism can lead to a spectrum of disorders, such as thyroid hormone resistance syndrome, caused by mutations in TRβ that diminish the binding to T3 (17), or hypothyroidism, resulting from mutations in TRα1 (18, 19). Furthermore, such disruptions may also heighten the susceptibility to certain cancers (20, 21). We conducted a thorough review of various in vitro and preclinical models that investigated the effects of TRs, including TRβ and TRα1, on cancer development and progression. These studies examined how TRs influence cancer cell proliferation, as well as differentiation, the mechanisms by which cancer cells are transformed into undifferentiated cell types. We further explored their effect on tumor growth in preclinical models and their role in cancer stem cell activity, which is crucial for understanding tumor initiation and resistance to therapy. Based on our analysis, we proposed a pivotal hypothesis: TRs may function as tumor suppressors in cancer progression. This notion is based on the accumulated evidence that TRs regulate critical pathways involved in maintaining cellular homeostasis and inhibiting malignancy, providing new insights into therapeutic strategies for cancer treatment. This review places particular emphasis on unraveling the critical roles TRs play in the initiation, progression, and metastasis of various cancer types, highlighting their importance as potential therapeutic targets in oncology.
Thyroid Hormone Receptors Act as Tumor Suppressors in Preclinical Mouse Models
Accumulated evidence demonstrates that TR mutations are associated with human cancers, including hepatocellular carcinoma, renal cell carcinoma, breast cancer, and pituitary tumors (22-25). Dysregulated expression of TRs is often found in squamous lung cancer (26). Experimental data supporting the role of TRs as tumor suppressors in animal models provide valuable insights into the mechanisms underlying their antitumor effects. The first report of potential TRβ tumor-suppressor activity was discovered from studies of a mouse model of resistance to thyroid hormone β (RTHβ). In this mouse model, a dominant negative mutation (TRβPV), which has a frameshift mutation in the C-terminal 14 amino acids of TRβ, was targeted to the Thrb locus (27). The ThrbPV/+ mice model replicates symptoms in human RTHβ (28). Notably, homozygous ThrbPV/PV mice develop metastatic follicular thyroid carcinoma (FTC) with features including capsular and vascular invasion, anaplasia, and lung and heart metastases (Fig. 1) (27). In contrast, heterozygous ThrbPV/+ mice, which do not develop cancer, indicate that the wild-type (WT) Thrb allele may act as a tumor suppressor. ThrbPV/− mice, lacking the WT Thrb allele, show FTC progression similar to ThrbPV/PV mice, reinforcing that the WT Thrb allele serves as a tumor suppressor (29). Additionally, mice with both Thrb alleles knocked out develop FTC, further supporting the role of TRβ as a tumor suppressor in thyroid cancer (30).
Studies of other types of cancer also support that TRs act as tumor suppressors. In one study, experimental 2-stage skin carcinogenesis was induced by a carcinogen, 7, 2-dimethylbenz[a]anthracene (DMBA) and a promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA). After treatment for 20 weeks, tumor growth in the mice deficient of all functional TRs was significantly faster. Interestingly, skin tumors from TR knockout mice had a more malignant phenotype. In WT mice, more than 80% of tumors were usually well-differentiated papillomas, whereas in knockout mice, 50% of tumors exhibited indications of in situ carcinoma and squamous cell carcinoma accounting for a quarter of the total tumor population. This suggests that endogenous TRs restrain malignant progression in the mouse model of epithelial carcinogenesis (31).
Genetically engineered mice with combined mutations in TRs and other tumor suppressors have been used to study the cooperative effects of TR loss and other genetic alterations in cancer development. In ThrbPV/PVPten+/− mice, TR mutations and PTEN deficiency accelerated the progression of FTC and increased the occurrence of metastasis spread to the lungs, thereby significantly further reducing their survival, as compared with ThrbPV/PV mutation only (32). In these mice, the TR mutation markedly increased the risk of mammary hyperplasia with high susceptibility to mammary tumors, as evidenced by the occurrence of mammary hyperplasia in approximately 60% of ThrbPV/+Pten+/− mice and approximately 77% of ThrbPV/PVPten+/− mice vs approximately 33% of Thrb+/+Pten+/− mice (33). It was also shown that mutations in TRs cooperated with other oncogenes to promote cancer development. ThrbPV/PVKrasG12D mice exhibited poorer survival due to more aggressive pathological progression at an earlier age and at a higher frequency of lung metastasis than ThrbPV/PV mice (Fig. 2). Importantly, these mice developed frequent anaplastic foci with complete loss of normal thyroid follicular morphology, indicating that the TR mutant cooperated with the mutant Kras gene to propel cancer progression via the loss of tumor-suppressing function of WT TRβ (34).
Hematoxylin-eosin staining of thyroids, lung, or heart shows pathologic progression of thyroid carcinoma of ThrbPV/PVKrasG12D mice. A) Hyperplasia; B) capsular invasion and vascular invasion; C) and D) anaplastic foci; E) microscopic lung metastases (Met); and F) heart metastases (Met) in the mice at age 2 to 5 months. [Reproduced from Zhu et al (34)].
Mouse xenograft models, where human cancer cells are implanted into immunocompromised mice, have been used to assess the roles of TRβ on tumor growth and metastasis. In hepatocarcinoma and breast cancer cells, exogenously expressed TRβ reduces tumor growth, causes partial mesenchymal-to-epithelial cell transition, and has a striking inhibitory effect on invasiveness, extravasation, and metastasis formation in mice (31). Exogenously expressed TRβ in a FTC cell line, FTC-133 cells, reduced cancer cell proliferation and impeded migration of tumor cells. TRβ expression in FTC-133 and FTC-236 led to decreased tumor growth and reduced new vessel formation (35). In a human breast cancer cell line MCF-7, the estrogen-dependent growth of MCF-7 cells was inhibited by the expression of TRβ in the presence of T3. In a xenograft mouse model, large tumors rapidly developed after inoculation of control MCF-7 cells. In contrast, markedly smaller tumors (98% smaller) were found when TRβ-expressing MCF-7 cells were inoculated, indicating that TRβ inhibited the E2-dependent tumor growth of MCF-7 cells (36). In human colorectal cancer cells, cell proliferation and migration were significantly inhibited by TRβ overexpression in vitro (37). In aggressive anaplastic thyroid cancer (ATC), restoration of TRβ expression in the human ATC cell line SW1736 reduced the aggressive phenotype, decreased cancer stem cell populations, and induced cell death in a T3-dependent manner (38). The suppression of tumor growth by TRβ is clearly illustrated in tumor growth of human ATC cell line THJ-11T cells (designated as 11T cells) (39). Tumors induced by parental 11T cells grew rapidly, whereas no visible growth was detected in TRβ-expressing 11T cells. Tumor weight from inoculation of 5 × 106 11T cells or TRβ-expressing cells showed that 11T-induced tumors weighed an average of 500 mg, while TRβ-expressing 11T cells merely formed the nodule with a few milligrams of tumor tissues (39). In tumor induction experiments using gradually diluted parental 11T cells in nude mice, tumors appeared at every cell count injected, although tumor size consistently diminished with lower cell counts. In contrast, inoculating TRβ-expressing 11T cells at the highest count resulted in only barely visible tumors (39). These data strongly support that TRβ acts as a tumor suppressor.
While most of the studies are focused on TRβ, TRα1 has also been shown to have tumor-suppressive functions. In 2 human ATC cell lines, 11T and THJ-16T (designated as 16T) cells, the exogenously expressed TRα1 inhibited ATC cell proliferation and induced apoptosis. In xenograft mouse models, the expressed TRα1 resulted in marked tumor growth inhibition with reduced cell proliferation and increased apoptosis (40).
These accumulated experimental data from preclinical mouse models support that both TRβ and TRα1 act as tumor suppressors by inhibiting tumor initiation, progression, and metastasis. These findings have important implications for understanding thyroid hormone signaling in cancer biology and for developing TR-targeted therapeutic strategies for cancer treatment.
Effects of Thyroid Hormone Receptors on Oncogenic Signaling Pathways
Understanding the molecular mechanisms of TRβ action in cancers is crucial for elucidating its roles in tumor suppression and identifying potential therapeutic targets. TRβ, functioning as a transcription factor, integrates molecular signals from hormone levels, cellular pathways, and modifications to coordinate gene regulation. It interacts with various coregulators, influencing cellular homeostasis and tumor suppression. Several coactivators, including the steroid receptor coactivator, p300/CBP histone acetyl transferases, and the mediator-like TR associated proteins (TRAP/DRIP), assist in T3-dependent gene activation by TRβ (41, 42). They facilitate histone acetylation and recruit RNA polymerase II, promoting transcriptional activation. TRβ also associates with nuclear corepressors, like nuclear corepressor 1 (NCoR1) or silencing mediator for retinoid or TRs (SMRT, NCoR2), to suppress gene expression (43). These corepressors recruit histone deacetylases, which is crucial for gene repression. Disruption of these interactions in cancer cells can impair T3 response or lead to abnormal transcription, triggering abnormal activation of oncogenic signaling pathways.
Phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/AKT) signaling is a potent tumor-activating pathway (44). The PI3K-AKT pathway is a vital intracellular signaling cascade implicated in cell growth, survival, and metabolism (45). It is initiated by the activation of PI3K in response to extracellular signals, leading to the generation of phosphatidylinositol 34,5-trisphosphate (PIP3). PIP3 recruits and activates AKT, which in turn phosphorylates downstream targets, regulating processes such as protein synthesis, cell proliferation, and apoptosis evasion. Primary human thyroid cancer specimens often show AKT overexpression and overactivation (46, 47). In the ThrbPV/PV mice that spontaneously developed thyroid cancer, AKT was hyperphosphorylated both in primary thyroid and metastatic tumors. It was demonstrated that PV-mutant TR bound significantly more to the PI3K-regulatory subunit p85α, resulting in a greater increase in the kinase activity than TRβ did in WT mice (48). In primary thyroid cell lines derived from ThrbPV/PV mice, reduction of phosphorylated AKT levels or AKT downstream targets diminishes cell motility (49). Reduced AKT signaling is associated with delayed tumor progression and prolonged survival (50). In human follicular cancer FTC-133 cells, exogenously expressed TRβ, as compared with control FTC cells lacking TRβ, reduced cancer cell proliferation and impeded migration of tumor cells through inhibition of the AKT-mTOR-p70-S6K pathway. TRβ expression in FTC-133 and FTC-236 led to less tumor growth in xenograft models (35). In human colorectal cancer cells, it was also shown that TRβ suppresses proliferation and migration by inhibiting PI3K/AKT signaling (37). In ATC cell lines, TRβ suppresses PI3K signaling. The reintroduction of TRβ in ATC cell lines enabled an increase in the efficacy of the competitive PI3K inhibitors on cell viability, migration, and suppression of PI3K signaling (51). These reports suggest that TRβ could interrupt PI3K-AKT signaling, potentially hindering cancer development and progression.
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a vital signaling cascade implicated in numerous cellular processes, including growth, differentiation, and immune response (52). It begins with the activation of JAKs by extracellular cytokines or growth factors binding to their respective receptors. Once activated, JAKs phosphorylate and activate STAT proteins. Phosphorylated STAT proteins dimerize, translocate to the nucleus, and regulate the transcription of target genes involved in various cellular functions. Dysregulation of the JAK-STAT pathway is associated with diseases such as cancer. In a xenograft mouse model of the human breast cancer cell line MCF-7, it was shown that the TRβ mediated the inhibition of tumor growth via downregulation of the JAK-STAT-cyclin D pathways (36). In ThrbPV/+Pten+/− mice with development of mammary hyperplasia, TR-mutant PV increased the activity of STAT5 to increase cell proliferation and the expression of the STAT5 target gene encoding β-casein in the mammary gland. In the breast cancer cell line T47D cells, T3 repressed STAT5 signaling in TRβ-expressing cells through decreasing STAT5-mediated transcription activity and target gene expression, whereas sustained STAT5 signaling was observed in TRβPV-expressing cells, indicating that TRβ mutation promotes the development of mammary hyperplasia via aberrant activation of STAT5 (33).
Transforming growth factor β (TGFβ) signaling is a crucial pathway involved in regulating various cellular processes, including cell growth, differentiation, and immune responses (53). Upon binding of TGFβ ligands to their receptors, a signaling cascade is initiated, leading to the phosphorylation of mothers against decapentaplegic homologue (SMAD) proteins. Phosphorylated SMAD proteins form complexes that translocate to the nucleus, where they regulate the transcription of target genes, affecting diverse biological functions and contributing to tissue homeostasis and development. In the MCF-7 cells, it was observed that T3-liganded TRβ could attenuate TGFβ-induced phosphorylation of SMAD2 and SMAD3, thereby reducing their transcriptional activity (54). This attenuation of TGFβ signaling is a notable and conserved characteristic of liganded TRβ, emphasizing the TRβ role as a potent and broad-spectrum tumor suppressor.
Taken together, the molecular mechanisms underlying TRβ action in cancer involve its regulation of gene expression and interaction of TRs with other oncogenic pathways. Understanding these mechanisms provides insights into the complex roles of TRβ in cancer biology and may lead to the development of novel strategies for cancer prevention and treatment.
Roles of Thyroid Hormone Receptors in Stem Cell Activity
Stem cells are undifferentiated cells with the remarkable ability to self-renew and differentiate into specialized cell types. They play crucial roles in normal tissue development, maintenance, and repair throughout life. However, when the regulatory mechanisms governing their growth and differentiation go awry, stem cells can contribute to the initiation and progression of cancer. Cancer stem cells (CSCs) are a subset of cells within tumors that share characteristics with normal stem cells, including self-renewal and multipotency. CSCs have been implicated in tumor progression, metastasis, and therapy resistance (55).
Thyroid hormone receptors could act as tumor suppressors through inhibition of cancer stem cell activity. During dedifferentiation, aggressive cancers adopt a more stem-like phenotype, granting them indefinite replicative capacity and the ability to evade immune surveillance. TRβ has been shown to diminish the stem cell pool in breast and thyroid cancers. It was demonstrated that TRβ activation in MCF-7 cells reduced mammosphere formation, coinciding with decreased expression of breast stem cell markers ALDH1 and CD44 and increased expression of CD24, a marker associated with monolayer growth (54). TRβ manipulation led to reduced expression of downstream targets of CD44 and TGF signaling, including SOX2 and NANOG.
In ATC, it was investigated whether TRβ expression and T3 treatment could mitigate the stem-like characteristics of SW1736 cells (38). Notably, treatment with T3 led to a reduction in anchorage-independent colony growth in control SW1736-EV cells, while virtually eliminating colony growth in the SW1736-TRβ. Significant downregulation of stem cell markers, such as ALDH, OCT3/4, CD44, SSEA-1, and PROM1, was observed. Furthermore, TRβ expression in ATC cells resulted in stem cell death, increased CD24 expression, and decreased CD44 expression, enhancing the efficacy of inhibitors targeting PI3K, mitogen-activated protein kinase, and cell cycle progression in the stem cell population.
ATC is an aggressive thyroid cancer that is resistant to current treatments (56). Using human ATC cells. TRβ's effect on CSC activity was evaluated (39). TRβ was shown to inhibit CSC activity by diminishing tumorsphere formation and tumor-initiating capacity in human ATC cells. Using single-cell transcriptomic analysis, TRβ was shown to suppress the expression of key CSC regulators in ATC-induced xenograft tumors, such as ALDH, KLF2, SOX2, β-catenin, and ABCG2. Furthermore, ATC cells (11T cells) lacking TRβ, when inoculated into nude mice, developed tumors sized according to the cell number inoculated. At each corresponding cell number, 11T-TRβ–expressing cells induced markedly smaller tumors (Fig. 3) due to CSC-suppressing effects of TRβ. Thus, TRβ acted to suppress the expression of key CSC markers, resulting in reduced CSC activity to mitigate tumor development. These findings highlight TRβ's role as a novel transcriptional regulator to regulate CSC activity, thereby demonstrating its therapeutic potential in the treatment of ATC.
Thyroid hormone receptor β (TRβ) reduces anaplastic thyroid cancer tumor growth in nude mice following inoculation with different numbers of cancer cells. As inoculated cell number increased, tumor size also increased. TRβ-expressing cells (11T-TRβ #3 and 11T-TRβ #11) induced significantly smaller tumors compared to 11T cells at corresponding cell numbers. [Reproduced from Lee et al (39)].
To investigate whether effective treatment of ATC is associated with diminished stem cell activity, the effect of inhibiting cyclin-dependent kinase 7 (CDK7) on ATC advancement and CSC activity was investigated (57). The effect of the CDK7 inhibitor THZ1 on CSCs was assessed in human ATC cell lines (11T and 16T) and xenograft mice models. Our investigation revealed the NOTCH1-cMYC signaling axis as a primary target of CDK7 inhibition in ATC. By blocking NOTCH1-cMYC signaling with crenigacestat, a significant decrease in CSC capacities was observed in ATC, as indicated by impaired tumorsphere formation, reduced aldehyde dehydrogenase activity (a CSC marker), and suppressed tumor initiation and growth. Additionally, diminished CDK7 expression was associated with prolonged disease-free survival in thyroid cancer patients. These findings underscore the importance of NOTCH1 as a key regulator of CSCs and suggest that targeting the NOTCH1-cMYC signaling pathway is a promising therapeutic approach for ATC by modulating stem cell activity.
Reexpression of endogenous TRβ has emerged as a promising therapeutic avenue for ATC by targeting CSC activity (58). The demethylation agent decitabine was used as treatment in human ATC tumors and effectively reactivated endogenous TRβ expression. The resulting TRβ expression not only impeded cell proliferation by halting cells at the S phase, but also enhanced apoptotic cell death by upregulating cleaved caspase-3. Moreover, it significantly curbed the expression of CSC regulators, such as cMYC, ALDH, SOX2, CD44, and β-catenin. The treatment of decitabine in nude mice inhibited xenograft tumor growth by suppressing CSC activity, reducing cancer cell proliferation, and promoting apoptosis (58). These findings underscore the potential of reexpressing endogenous TRβ as a novel therapeutic strategy for ATC through the inhibition of CSC activity.
Effects of Thyroid Hormone Receptors on Redifferentiation in Cancer
Dedifferentiation is a crucial process in cancer progression where mature, specialized cells lose their specialized functions and revert to a less differentiated state. This regression often results in increased cell proliferation, invasiveness, and resistance to treatment (59). Dedifferentiated cancer cells exhibit enhanced plasticity, allowing them to adapt to different microenvironments and acquire new traits, such as drug resistance and metastatic potential. This process fuels tumor growth, progression, and the development of more aggressive phenotypes.
Dedifferentiation is the key feature of aggressive thyroid tumors with immune evasion and therapeutic resistance. Therefore, the induction of differentiation in thyroid cancer is a desirable approach to control tumor growth. It was reported that T3 or TRs could induce the reexpression of normal tissue-specific differentiation markers (38, 60, 61). In thyroid cancer, the differentiation markers include iodothyronine deiodinase 2 (DIO2), dual oxidase 1 (DUOX1), thyroid peroxidase (TPO), thyroglobulin (TG), and the sodium iodide symporter (NIS). Of note, the TRβ agonist sobetirome (GC-1) reduced the tumorigenic phenotype, decreased cancer stem-like cell populations, and induced redifferentiation of the ATC cell lines with different mutational backgrounds. The selective activation of TRβ amplified the effects of therapeutic agents in blunting the aggressive cell phenotype and stem cell growth (61). The effect of GC-1 on ATC cell lines also suggests that T3 levels, particularly within tumors, may play a crucial role in the ability of TRs to suppress cancer progression. Type 3 deiodinase (DIO3, or D3) is an enzyme that locally inactivates T3 in a tissue-specific fashion (62). It remains largely inactive in normal adult tissues but is highly expressed in cancers. Overexpression of D3 has been detected in a range of immortalized cell lines derived from different cancers (63). D3 overexpression is associated with several adverse outcomes, such as local hypothyroidism, enhanced cellular proliferation, increased tumor growth, altered metabolic phenotype, and greater aggressiveness. Notably, elevated D3 levels in papillary thyroid carcinoma are associated with increased tumor size and metastatic disease (64). Therefore, it is reasonable to argue that WT TRs might function as tumor suppressors only in the presence of T3, given that most in vitro and in vivo studies have been conducted in a euthyroid state, without inducing hypothyroidism.
TRα1 orchestrates thyroid hormone genomic actions. However, its involvement in cancers remains unclear. Analysis of The Cancer Genome Atlas (TCGA) revealed loss of THRA gene expression in highly dedifferentiated ATC, prompting exploration of TRα1's effects on ATC progression. Expressing TRα1 in 2 ATC cell lines led to a substantial reduction in cell proliferation, triggered apoptosis, and reduced tumor size in nude mice (Fig. 4). Importantly, there was a significant correlation between THRA gene expression and PAX8, a marker associated with thyroid differentiation, which exhibited upregulation in TRα1-expressing cells at both messenger RNA and protein levels. Molecular analyses revealed TRα1's direct influence on PAX8 expression regulation. Furthermore, single-cell transcriptomic investigations underscored TRα1's function as a transcription factor, coordinating various signaling pathways to inhibit tumor progression and enhance differentiation. These findings underscore TRα1 as a potential therapeutic target for enhancing ATC patient outcomes by promoting thyroid differentiation (40).
A recent study further supported that TRα1 could function to redifferentiate not only highly dedifferentiated ATC, but also other cancer cells such as those in medulloblastoma (65), the most prevalent malignant brain tumor among children. Despite current multimodal therapy, a significantly high number of patients still succumb to this disease, highlighting the need for novel treatment strategies. Yang et al (66) recently reported that reduced T3 levels free TRα1 to bind to EZH2, a catalytic subunit of the polycomb repressive complex and histone methyltransferase, thereby repressing expression of NeuroD1, a transcription factor that promotes tumor differentiation. Reversely, elevated T3 levels abrogate the binding of TRα1 to EZH2, thereby inducing tumor differentiation via activating expression of NeuroD1, leading to suppression of tumor growth. These findings suggest that TRα1, via T3, may also function to activate other differentiation regulators in various cancers.
For the role of TRα1 in carcinogenesis, it is important to note that TRα1 may promote tumor growth under certain specific conditions. Specifically, overexpressing TRα1 in the intestinal epithelium of mice with WNT activation due to a mutation in the adenomatous polyposis coli (Apc+/1638N) gene can accelerate cancer progression, albeit TRα1 overexpression by itself does not induce cancer (67). This is particularly relevant as Apc mutation may lead to significant upregulation of β-catenin, which in turn could increase D3 activity (60), thereby altering local T3 levels. While the observation seems to suggest that TRα1 might have tumor-promoting effects when Apc is mutated, it could also be argued that sufficient local T3 might be necessary for overexpressed TRα1 to suppress tumor progression, since higher levels of D3 activity might cause local deficiency of T3. Therefore, this observation does not directly contradict our hypothesis that TRα1 could act as a tumor suppressor.
Conclusion
Exciting conclusions about the roles of TRs in cancers offer a glimpse into a promising future for cancer research and treatment. The recognition of TRs, particularly TRβ, as tumor suppressors across various cancer types represents a substantial advancement in our understanding of cancer biology. This discovery opens new avenues for targeted therapies aimed at restoring or enhancing TR activity to counteract tumorigenesis. By harnessing the tumor-suppressive functions of TRs, researchers envision novel treatment strategies that could complement existing therapies and improve patient outcomes.
The emerging field of TR-targeted therapies holds immense potential for revolutionizing cancer treatment. Small-molecule agonists, gene therapy approaches, and combination therapies targeting TRs and oncogenic pathways are being explored in preclinical studies and clinical trials. For example, decitabine has been approved for treating certain types of cancer, such as myelodysplastic syndromes and acute myeloid leukemia, and is being evaluated for the treatment of various other cancers beyond its approved uses. We have shown that decitabine-induced endogenous TRβ expression in ATC cells inhibits cell proliferation, enhances apoptosis, reduces cancer stem cell activity, and suppresses tumor growth. It may also be evaluated in combination with currently approved drugs for treating ATC. The T3 analogue GC-1 is highly specific for TRβ (68). In cases where local T3 deficiency is caused by increased D3 activity, this analogue may be used to stimulate TR activity. We previously demonstrated that increased expression of MYC is critical in ATC progression (34). Currently, many small molecules targeting MYC are available (69). These molecules could be evaluated for potential use in treating ATC. Additionally, emerging genomic editing technologies, such as CRISPR-Cas9 (70), make it possible to directly repair dysfunctional mutant TRs. These innovative treatment modalities offer the prospect of personalized medicine, where therapies can be tailored to individual patients based on their TR expression profiles and genetic backgrounds. With further advancements in TR-targeted therapies, we anticipate more effective and less toxic treatments that could transform the landscape of cancer care.
Acknowledgments
We would like to thank all our colleagues and collaborators who have contributed to the work described in this article. We regret any reference omissions due to length limitation. We thank Joelle Mornini, National Institutes of Health Library, for manuscript editing assistance.
Abbreviations
| ATC | anaplastic thyroid cancer |
| CDK7 | cyclin-dependent kinase 7 |
| CSCs | cancer stem cells |
| D3 | type 3 deiodinase |
| FTC | follicular thyroid carcinoma |
| GC-1 | sobetirome |
| JAK | Janus kinase |
| PI3K | phosphoinositide 3-kinase |
| PIP3 | phosphatidylinositol 3,4,5-trisphosphate |
| PKB/AKT | protein kinase B |
| RTHβ | resistance to thyroid hormone β |
| SMAD | mothers against decapentaplegic homologue |
| STAT | signal transducer and activator of transcription |
| T3 | 3,5,3′-triiodothyronine |
| TGFβ | transforming growth factor β |
| TR | thyroid hormone receptor |
| WT | wild-type |
Contributor Information
Xuguang Zhu, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Sheue-yann Cheng, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Funding
This work is supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (No. ZIA BC 011191).
References
Articles from Endocrinology are provided here courtesy of The Endocrine Society
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