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THYROID HORMONE RECEPTORS AND CANCER
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Agnieszka Piekielko-Witkowska
Department of Biochemistry and Molecular Biology, The Medical Center of Postgraduate Education, Warsaw, Poland
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Editorial 2009
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Reviewing Editor: Graham Williams
The Author declares no conflict of interest related to this manuscript.
Correspondence to:
Agnieszka Piekielko-Witkowska
Department of Biochemistry and Molecular Biology,
The Medical Center of Postgraduate Education,
ul. Marymoncka 99/103, 01-813 Warsaw - Poland
Email: pieklo@cmkp.edu.pl
ABSTRACT
Thyroid hormone receptors (TRs) belong to the family of nuclear receptors and act as ligand
dependent transcription factors. The ligand of TRs is 3,5,3’-triiodothyronine (T3). Recent reports
showed that TRs and T3 are involved in carcinogenesis and influence processes of differentiation,
proliferation, apoptosis, and metastasis. The supporting specific roles of TRs in tumorigenesis include
common aberrations of TRs action in cancers and results of experiments on animal models. Although
the majority of currently available data suggest the suppressive role of TRs in carcinogenesis, the fact
that TRs are overexpressed in several tumor types suggests that they may also act as cancer
promoting factors. This review discusses the mechanisms which are triggered by TRs to exert these
two opposite roles of TRs in carcinogenesis.
Thyroid hormone receptors: structure and function
Human thyroid hormone receptors are encoded by two genes, THRA and THRB, located in
17q11.2 and 3p24.2 chromosome regions, respectively. The primary transcripts of both genes
undergo several alternative splicing events, producing multiple protein isoforms of the receptors that
differ in amino-acid composition and biological properties. TRs share the common structure of the
nuclear receptors family with functional domains: A/B, C, D, E, and F (Fig.1). The C domain (or DBD,
DNA Binding Domain) is responsible for binding of specific sites at T3 responsive genes, called
Thyroid Hormone Response Elements (TREs). The E domain (LBD, Ligand Binding Domain) binds
T3 and mediates interactions with coregulatory proteins. Both domains participate also in dimerization
of the receptors. Heterodimerization with RXR (retinoid X receptor) is critical for activity of TRs.
Fig. 1. Structure of thyroid hormone receptors. Two main isoforms (TRα1 and TRβ1) are
shown, coded by genes THRA and THRB. DBD: DNA binding domain; LBD: ligand binding
domain. The percentage of conservation between domains of TRα1 and TRβ1 is shown. The other
TR isoforms were reviewed by Basset et al. (6).
The T3 responsive genes may be regulated in a positive or negative manner (1). The
mechanism of positive regulation is mediated by positive TREs and depends on recruitment of
coregulatory proteins that induce changes in chromatine structure, enabling transcriptional activation
by T3-bound receptors or repression when T3 is absent. The T3-dependent repression of negatively
regulated genes is less well understood. Currently several mechanisms are proposed, basing mainly
on transient transfection studies. One of such mechanisms includes binding of negative TREs which
act in an opposition to positive TREs. TRs may also negatively regulate the transcription without
binding to DNA due to interference with other transcription factors and acting as specific traps or baits
for coregulatory proteins (2).
TRs may also act in a nongenomic way (3). In this mode the TRs do not act as transcription
factors but rather regulate activity of other proteins due to direct interactions. The detailed structure,
function and mechanisms of TRs action have been extensively reviewed elsewhere (4 - 7).
A significant number of TRs regulated genes and proteins have been identified so far; many of
them are important regulators of cellular proliferation, differentiation and apoptosis (8). Thus, it is not
surprising that aberrations in functioning of TRs result in disturbances of cell physiology.
TRs and cancer
The first observations directly suggesting that TRs may be involved in carcinogenesis came
from studies on v-erbA gene, encoded by the avian erythroblastosis virus and causing acute
erythroleukemia and fibrosarcomas in chickens (9). TRα is the cellular homologue of v-ErbA protein,
product of the viral gene (10, 11). Compared to TRα v-ErbA bears several amino-acid substitutions,
partially located in DBD and LBD domains leading to loss of T3 binding and constitutive dominant
negative effect to transcription activation by TRs (12). The oncogenic potential of v-erbA was proved
in mice models developing hepatocellular carcinomas (13). Currently several mechanisms are
proposed to explain the v-ErbA contribution to tumor formation. v-ErbA interferes with TRs due to
competition for TRE or for TRs’ coregulatory proteins such as RXR (14). v-ErbA may also mediate
nuclear export of TRs preventing TRs mediated regulation of transcription in the nucleus (15). It was
also suggested that oncogenic activity of v-ErbA may result from the ability to recognize a distinct set
of target genes compared to the wild type receptors (16, 17).
The hypothesis that TRs may play a role in neoplastic transformation was supported by frequent
aberrations of expression and mutations of TRs coding genes in human cancers (Table 1). Types of
disturbances include aberrations in chromosomal regions of TR coding genes, epigenetic alterations,
mutations, and changes in TRs expression level. The mutations are located mainly in LBD and DBD
domains and result in significant disturbances of TRs action. Mutated TRs do not bind (or the binding
is weakened) T3 and/or DNA; interactions with coregulators are also disturbed. Mutated TRs inhibit
the activity of wild type receptors in a dominant-negative manner.
Table 1. Aberration of TRs found in human tumors. LOH: loss of heterozygosity.
Recent years brought significant advances in understanding the role of TRs in cancer development, tumor progression and metastasis reviewed in several excellent publications (50-54).
Interestingly, it appears that TRs may act both as pro- and anti-cancerous factors. These opposite
effects of TRs are discussed below.
TRs as cancer promoting factors.
Hepatocellular carcinoma is characterized by a high frequency of TRs alterations, including
truncations and mutations in TRα1 and TRβ1 cDNAs, resulting in aberrant binding of T3, DNA (39),
and protein coregulators (40, 41). The mutated TRs display a target gene repertoire distinct from that
of their normal TR progenitors (55). It was suggested that this “switch” in recognition of target genes
could possibly be directly responsible for oncogenic potential of mutated TRs as well as v-ErbA in
contrast to dominant-negative mutations of TRs found in inherited RTH syndrome (41). The other
studies show, however, that not only mutations but also changes in expression of wild type TRs may
contribute to tumorigenesis. For instance, elevated expression of TRβ1 protein was found in
hepatoma cells, suggesting its promoting role in carcinogenesis. TRα was shown to enhance
metastasis of human hepatoma due to upregulation of furin gene expression (56). Furin belongs to
the family of proprotein convertases (PCs) that activate their substrates via limited proteolysis. The
substrates of PCs family include several proteins involved in carcinogenesis; moreover, furin
expression is associated with enhanced invasion and proliferation of several types of cancer (57).
TRs positively regulate the expression of furin (56). Overexpression of TRs in hepatoma tumors leads
to upregulation of furin and results in enhanced activity of matrix metalloproteinases (MMPs). MMPs
catalyze degradation of extracellular matrix leading to increased tumor cell invasiveness. The effect of
T3 is further enhanced by TGF-β (transforming growth factor beta), which induces signal pathway of
MEK/ERK kinases. The latter enzymes catalyze the phosphorylation of TRs resulting in their stabilization (58) contributing to further stimulation of furin expression.
Another mechanism potentially contributing to pro-metastatic action of TRs in hepatoma is a
negative regulation of antimetastatic gene Nm23-H1 (59). Nm23-H1 is a nucleoside diphosphate
kinase (NDP) and a metastasis suppressor (60) whose lowered expression correlates with aggressive behavior of different types of cancer. Lin et al. (59) found that expression of TRα1 in HepG2 cell line
results in repression of Nm23-H1 and leads to increased invasiveness of cells.
There is no entirely satisfying model describing the exact role of T3 and TRs in hepatoma,
however. For instance, the same authors published conflicting results showing that T3 and TRs may
also play antitumor role in hepatoma (61, 62). There are also other examples of antitumor activity of thyroid hormones in hepatocellular carcinoma, discussed further in detail below.
TRs as tumor suppressors.
Antitumorigenic properties of tumor suppressors are often reflected by the effects of mutations
blocking their protective function. The proofs for the suppressive role of TRs in cancers include
findings that mice expressing a dominant negative TRβ mutant spontaneously develop thyroid and
pituitary tumors (63, 64), and mouse TR knockouts (TRKO) show increased aggressiveness of skin
tumors (65). The other arguments supporting the hypothesis are the loss of TRβ1 expression and
multiple other alterations resulting in loss of function of TRs in cancer tissues (see Table 1).
Mouse models of TRs action in cancer.
The first in vivo evidence suggesting that THRB gene may act as a tumor suppressor came
from knockin mutant mice harboring a PV mutation (63), originally identified in a patient with thyroid
hormones resistance (RTH) (66). This mutation results in complete loss of T3 binding by TRβ1 and, in
consequence, loss of ability to activate transcription by the receptor (67). Aging homozygous
(TRβPV/PV) mice spontaneously develop thyroid cancer (63), and TSH-secreting pituitary tumors (TSHomas)
(64), not observed in heterozygous or TRKO animals. Further studies on these mice revealed
several mechanisms controlled by TR in cancer development, described in detail below.
The function of PV mutant is severely disturbed compared to the wild type receptor. These
disturbances lead to activation of pro-proliferative signaling pathways and alterations in cell motility
contributing to increased survival, invasive and metastatic properties of cancerous cells. These effect
may be achieved via both non-genomic and genomic actions of the mutated receptor. At non-genomic
level the PV receptor interacts with several cellular regulatory proteins interfering with important signaling pathways. One of such regulators is phosphatydilinositol 3-kinase (PI3K), involved in a wide
group of processes essential for survival of the cell, such as metabolism, growth, and motility (68).
PI3K catalyses phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to form
phosphatidylinositol-3,4,5-triphosphate (PIP3), a potent activator of several protein regulators. TRβ1
binds p85α subunit of PI3K (69); the PV mutation, however, strengthens these interactions and leads
to intensified activation of PI3K downstream pathways including AKT–mTOR–p70S6k. Since p70S6k is
known to promote cell growth, cell cycle progression and to act as an anti-apoptotic factor (70 - 72)
the PV initiated activation of AKT–mTOR–p70S6k may result in progression of tumorigenesis.
The PV-induced activation of PI3K results in activation of ILK (integrin-linked kinase), and its
downstream target, metalloproteinase 2 (MMP-2) (69), involved in degradation of extracellular matrix
and playing a pivotal role in cell invasion and metastasis (73). Since another substrate of ILK is AKT
(74), the downstream pathways of PV activated PI3K may cross-talk with each other, leading to the
final activation of proliferation.
Another mechanism contributing to increased metastatic potential of thyroid cancer in TRβPV/PV
mice is interaction of TRβ1 with gelsolin (75), an actin binding protein involved in cytoskeleton
organization (76). Compared to the wild type receptor, the PV mutant disturbs interaction between
gelsolin and actin, resulting in improperties of cytoskeleton. As a consequence, the motility of cancer
cells is increased, contributing to metastatic potential of thyroid cancer (75).
The abnormalities commonly found in thyroid carcinomas include chromosomal aberrations (77-
80). Ying et al. (81) found that improper action of the mutated TRβ1 may contribute to these
alterations due to its interactions with PTTG1 protein. PTTG1 (pituitary tumor–transforming 1), called
also securin, is a multifunctional protein involved in cell division and DNA repair mechanisms (82, 83).
One of the important functions of PTTG1 is to ensure proper sister chromatid separation during
mitotic cell division. During metaphase, sister chromatids are held together by a mutiprotein complex
called cohesin. In anaphase, protein elements of cohesin complex are cleaved by protease called
separase and thus allow for cohesin dissociation from chromosomes. During other phases of the cell
cycle, separase is trapped by PTTG1 that inhibits its activity. At the metaphase to anaphase
transition, PTTG1 is degraded, leading to release of separase and destruction of cohesin complex (83). Ying et al. (81) found that
TRβ1 binds PTTG1 and regulates its degradation. T3 binding by
TRβ1-PTTG1 complex induces interaction with steroid hormone receptor coactivator 3 (SRC-3) and
binding of the latter with proteasome activator 28γ (PA28γ). This results in proteasome - mediated
degradation of TRβ1-bound PTTG1. The PV mutant, lacking ability of binding T3, does not form
complexes with SRC-3/PA28γ and inhibits PTTG1 degradation. PTTG1 overexpression results in
enhanced proliferation of hepatoma Hep3B cells and wild type TRs negatively regulate PTTG1
expression via Sp1 transcription factor (61). Concomitant observation that the expression of TRs in
human hepatocellular carcinoma is reduced along with elevated Sp1 and PTTG1 suggests that TRs
may play antitumoregenic role in human hepatoma. The same group, however, reported the opposite
effect of TRs, suggesting their prometastatic activity (discussed above, page 5). The conflicting
results of studies of the role of TRs in hepatoma are discussed on page 11.
TRβ1 regulates the stability of β-catenin, a multifunctional protein whose disturbed expression
was observed in different types of cancer (84). Acting as one of the elements of Wnt signalling
pathway, β-catenin functions as transcription factor controlling expression of a wide group of genes
involved in processes of proliferation, migration and survival. Action of β-catenin is regulated by
phosphorylation dependent ubiquitination and degradation. Inhibition of β-catenin phosphorylation
leads to its cellular accumulation and activation of transcription of downstream genes. Guigon et al., (85) found that TRβ1 interacts with β-catenin in a T3 dependent manner. T3 binding by TRβ1 leads to
release of β-catenin that can be directed for degradation. The PV mutant binds β-catenin, but since it
does not bind T3, the dissociation is blocked. This prevents β-catenin from degradation and leads to
its accumulation and constitutive activation of β-catenin signaling pathway. In consequence, the
expression of β-catenin regulated genes, such as c-myc oncogene, cyclin D1, and metalloproteinases
is changed in thyroid cancers of TRβPV/PV mice.
PV mutants exert their effects also at genomic level. A consequence of the PV mutation is
lowered expression of PPARγ receptor in thyroid cancers of TRβPV/PV mice (86). The PV mutant
interferes also with transcriptional activity of PPARγ receptor. Both TRβ1 and PV bind to PPRE
(PPARγ response elements) as heterodimers with RXR (retinoid X receptor) and compete with
binding of PPARγ/RXR. This competition leads to repression of transcription of PPRE regulated reporter gene. T3 presence leads to derepression mediated by TRβ1/RXR complex. The PV mutant,
however, lacks the ability of binding T3, therefore the PV/RXR constitutively represses expression of
PPRE regulated genes. Since the activation of PPARγ mediated expression is known to exert
antiproliferative effect (87), loss of PPARγ activity due to interference with mutated TRβ1 receptor
may contribute to tumorigenesis of thyroid cancer in TRβPV/PV mice.
Specific effects of PV mutants are also observed in pituitary tumors secreting TSH (TSH-omas)
of TRβPV/PV mice. Furumoto et al., (64) found that TRβ1 negatively regulates the expression of cyclin
D1 due to interference with CREB mediated activation of transcription. CREB (CRE binding protein) is
a transcription factor binding CREs (cyclic AMP response elements) located in promoters of
numerous genes (88). CRE- bound CREB interacts physically with both PV and wild type TRβ1 (64,
89) . In the presence of T3, TRβ1-CREB interaction is stronger, and so is the repression of
transcription. PV-mediated repression of transcription is not possible, leading to constant stimulation
of cyclin D1 expression. Another mechanism contributing to cyclin D1 upregulation in pituitary tumors
of TRβPV/PV mice is activation of AKT with consecutive phosphorylation of GSK-3β and inhibition of
kinase activity of the latter, preventing from phosphorylation of cyclin D1 and its proteasomal
degradation (90). This leads to activation of cyclin-dependent kinases (CDK4 and 6) and
hyperphosphorylation of retinoblastoma protein (Rb) (64). Since TRβ1 mutations, as well as
disturbances in expression of cyclin D1 are found in pituitary tumors (18-21, 91), the murine model of
TRβ1 role in pituitary tumors sounds very plausible.
The studies on mutant mice raised the question whether the observed tumorigenesis results
from loss-of-function or gain-of-function of PV mutation. Recent work by Zhu et al. (92) addressed this
problem. They showed that the mice devoid of all known functional TRs (TRα1-/-TRβ1-/-) spontanuosly
develop follicular thyroid cancer as they age. This study provides direct evidence that TRs in mice
could function as tumor suppressors in vivo.
Anticancer effects of TRs in human cells.
Apart from mouse models, important information on the role of TRs in cancer comes from
investigations on human cancer tissues and cell lines. The vast majority of studies on antitumoral activity of TRs are focused on TRβ1 isoform. This could suggest that among the two isoforms TRβ1 is
the one that controls expression of protein regulators engaged in majority of pathways contributing to
protection against cancer. These different biological roles of TRs isoforms could possibly result from
the ability to regulate different groups of genes. Chan and Privalsky (93) showed, however, that in fact
the set of genes regulated by TRα1 and TRβ1 overlap in HepG2 cells. Moreover, it seems that
different functional properties of the two receptors result rather from isoform-specific range of T3-
mediated transcriptional regulation. Thus, different biological functions of TRs result probably from
subtle changes in expression of TRs regulated genes. This is in agreement with the hypothesis of
procancerous effects of disturbed expression of TRs.
Aberrantly expressed TRs may lead to deregulation of proteins controlling cell cycle, such as
E2F1 (94). Clear cell renal cell carcinoma is characterized by the presence of mutations and
disturbances of expression of both TRs (46, 47). The mutations lead to severe improperties in TRs
function, including disturbances in binding of T3, DNA and coregulatory proteins (46, 48). E2F1 is a
transcription factor controlling G1 to S phase transition whose expression is negatively regulated by
TRs (95). The expression of E2F1 is increased in renal cancer tissues, what is in concomitance with
disturbed function of TRs. Since E2F1 is an important regulator of cellular proliferation (96, 97) its
disturbed expression may potentially contribute to renal tumorigenesis. In addition, T3 differently
affects proliferation of normal and cancerous kidney cells (98). While T3 treatment of cancerous cells
stimulates G1 to S phase progression, its effect in normal kidney cells is opposite, leading to inhibition
of proliferation. This effect is mediated by different T3-regulated expression of key cell cycle
regulators (E2F4, E2F5, p107 and p130).
Yen et. al (62) found that T3 inhibits proliferation of hepatoma HepG2-TR cell line (Fig. 2A.). In
these cells T3 stimulates the activity of promoter and expression of TGF-β. Upregulation of TGF-β
results in repression of cell cycle regulating proteins: cdk2, cyclin E and ppRb (hyperphosphorylated
retinoblastoma protein), and contributes to inhibition of cell proliferation. As discussed earlier, studies
investigating the role of thyroid hormone in hepatoma generated conflicting results and the same
group showed also that T3 may promote metastasis of hepatoma (56, 59). In opposition to this, Chan
and Privalsky (41) found that while ectopic expression of TRα1 in HepG2 cell line inhibits anchorage independent growth, the mutated TRα1 does not exert this effect. The antitumor role of T3 in liver
cancers is also supported by the observation that hypothyroidism is a possible risk factor for
hepatocellular carcinoma in patients with no known underlying cause of liver disease (99). This is in
agreement with experiments in rats showing that although T3 treatment induces liver proliferation, it
also leads to loss of hepatocellular carcinoma nodules, possibly due to redifferentiation of nodular
hepatocytes (100). In both studies the specific role of TRs was not analyzed, however, therefore it is
difficult to get the clear picture of their antitumor activity in these models. The conflicting results of
studies in hepatoma suggest that the final role of TRs in liver cancer may depend on the molecular
context within tumor cell and cooperation with other cellular regulators. It is known that tumor
microenvironment may influence the activity of tumor suppressors to result in switch into their
oncogenic function (101). Interestingly, one of the TRβ1 interacting partners, TGFβ, exerts such a
dual tumor suppressive-or oncogenic character (102). Therefore, further studies are needed focused
on the influence of tumor microenvironment and molecular context on TRs function in hepatic cancer.
TRβ1 mediates inhibition of Na2-β neuroblastoma cell line proliferation and induction of
morphological differentiation by an arrest in G0/G1 (103). TR expression leads also to the rasoncogene
mediated suppression of tumor formation in vivo in nude mice (104) (Fig. 2B.). The
expression of Ha-rasval12 oncogene activates transcription of cyclin D1 via kinase Rsk2 mediated
mechanism, leading to enhanced proliferation. T3 inhibits Rsk2 activity, expression of both TRα1 and
TRβ1 and reduces transforming ability of ras oncogene. TRβ1, however, exerts stronger
antiproliferative effect and is able to inhibit ras-mediated transformation even in the absence of T3
and to totally abolish tumor formation by ras-transformed cells in nude mice.
One of the few examples showing antitumor activity of TRα1 was published by Lee et al. (105).
In this study induced expression of TRα1 in nasopharyngeal carcinoma cells reduced proliferation,
colony-formation ability in agar, and tumor formation ability in nude mice.
Fig. 2. TRs as anticancer factors. A. Antiproliferative effect of TR/T3 stimulated expression
of TGFβ in hepatoma cell line. B. TR-mediated inhibition of ras-induced proliferation in
neuroblstoma cell line. C. TR antimetastatic action in hepatocarcinoma and breast cancer cell
lines. See text for details.
The ultimate evidence that TRβ1 may act as a potent tumor suppressor of tumor invasiveness
and metastasis in hepatocarcinoma and breast cancer came from Martinez-Iglesias et al. (65). They
showed that re-expression of TRβ1 in cells that have lost TR expression leads to tumor growth
retardation, partial mesenchymal to epithelial transition and strongly suppresses invasiveness,
extravasation and metastasis formation in nude mice. TRβ1 expression suppresses expression of
IGFR and EGFR, the receptors of key growth factors activating signaling pathways of ERK and PI3K.
TRβ1 also reduces expression of other downstream elements of these signaling pathways, and
blocks TGF-β dependent activation of MAPK and PI3K. In consequence, the expression of genes
involved in metastatic growth is repressed (65). Interestingly, experiments in nude mice suggest that
TRs play diverse roles at different stages of tumorigenesis. TRs deficiency inhibits benign tumor
formation at early stages of carcinogenesis but increases malignant transformation at later stages
(65). The same group showed also that hypothyroidism in mice affects invasiveness and formation of
metastasis independently of the cellular expression of TRβ1 (106). The thyroidal state has dual effect
on tumorigenesis. Hypothyroidism retards growth of tumor but results in its enhanced
aggressiveness, invasiveness, and metastasis formation. This is observed both in cells that express
and do not express TRβ1, suggesting that the role of thyroidal status in tumorigenesis is much more
substantial than direct TRβ1 mediated action on tumor cells.
Conclusions and future perspectives.
The role of TRs in cancer appears to be complex. Apart from strong evidence for
antitumorigenic actions the receptors may also trigger pro-metastatic mechanisms. These effects of
TRs possibly result from tissue-type and cancer-stage specific cross-talks with elements of cellular
signaling cascades such as PI3K/AKT/mTOR or MAPK. Studies providing information that TRs may
act as antitumor factors yield basis for hypothesis that TRs may be an interesting target for therapy.
This has been recently tested by Perra et al. (107) who showed that T3 and a selective TRβ agonist
causes regression of hepatocellular carcinoma nodules in rats.
In conclusion, although multiple mechanisms of TRs action in cancers have been identified,
future studies are needed to explain the complexity of interactions deciding on antiproliferative or
prometastatic actions of TRs.
Acknowledgements:
I wish to thank Prof. Alicja Nauman for critical reading of the manuscript, helpful discussions and continuous
support.
The financial support of the Medical Centre of Postgraduate Education (grant 501-2-25-01/09) is also
acknowledged.
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