Thyroid receptor: roles in cancer

Aranda, Ana; Martínez-Iglesias, Olaia; Ruiz, Lı́dia; García-Carpizo, Verónica; Zambrano, Alberto

doi:10.1016/j.tem.2009.03.011

Cited by 90 publications

(68 citation statements)

References 66 publications

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“…The results revealed a significant decrease in NCoR mRNA in tumors compared with normal liver, whereas no differences in SMRT mRNA levels were found. TRβ transcripts also were reduced in the HCCs, and Dio1, a bona fide TR target gene in liver cells (23), showed a similar reduction (Fig. 5B).…”

Section: Ncor Andmentioning

confidence: 66%

“…We have shown that this receptor retards tumor growth and suppresses invasion, extravasation, and metastasis formation in nude mice (23)(24)(25)(26). These tumor-suppressing effects are associated with a decreased expression of prometastatic genes (23).…”

mentioning

confidence: 91%

“…TRs, and in particular TRβ1, can act as tumor suppressors (23). We have shown that this receptor retards tumor growth and suppresses invasion, extravasation, and metastasis formation in nude mice (23)(24)(25)(26).…”

mentioning

confidence: 92%

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Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

Martínez-Iglesias

Alonso-Merino

Gómez-Rey

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor β1 (TRβ) appears to be associated with cancer onset and progression. We found that expression of TRβ increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRβ. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies.nuclear corepressor 1 | thyroid hormone receptor | tumor growth | metastasis | transcription

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Section: Ncor Andmentioning

confidence: 66%

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confidence: 91%

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Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

Martínez-Iglesias

Alonso-Merino

Gómez-Rey

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, we have recently shown that this receptor acts as a suppressor of invasiveness and metastasis formation by hepatocarcinoma cells (Martı´nez-Iglesias et al, 2009a, b), suggesting that it could represent a potential therapeutic target in cancer (Aranda et al, 2009). Recently, it has been shown that TRs could function as tumor suppressors in a mouse model of metastatic follicular thyroid carcinoma (Zhu et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Thyroid hormone receptor β1 domains responsible for the antagonism with the ras oncogene: role of corepressors

et al. 2010

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The thyroid hormone receptor (TR) is a suppressor of rasmediated responses. To characterize the receptor domains involved in this function, we analyzed a panel of TRb1 mutants for their ability to interfere with ras-driven cyclin D1 activation, formation of transformation foci and tumor growth in nude mice. Our results show that the domains and mechanisms responsible for the anti-transforming and anti-tumorigenic actions of the receptor are divergent from those operating in classical T3-dependent transcriptional activation. TRb1 mutants that do not bind coactivators and do not transactivate retained the capacity of suppressing cellular transformation and tumor growth, whereas selective mutations in the hinge region affecting corepressors recruitment abolished these actions, while preserving ligand-dependent transcription. There was a strict parallelism between anti-transforming activity of the various mutants and their ability to antagonize cyclin D1 stimulation by ras, indicating that transrepression mechanisms may have an important function in suppression of the transforming effects of the oncogene by TRb1. The inhibitory action of T3 on transformation was further enhanced after over-expression of corepressors, while corepressor depletion by means of small-interference RNA reversed significantly hormonal action. This shows an important functional role of endogenous corepressors in suppression of ras-mediated transformation and tumorigenesis by TRb1

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“…TRs can also modulate expression of genes that do not contain a hormone response element by modulating the activity of other transcription factors and signaling pathways (2), including activator protein-1 (AP-1)-, cyclic AMP-response element-, and nuclear factor-B (NF-B)-dependent pathways (3)(4)(5)(6)(7).…”

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confidence: 99%

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Contreras‐Jurado

García-Serrano

Gómez-Ferrerı́a

et al. 2011

Journal of Biological Chemistry

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The actions of thyroid hormones are mediated by binding to nuclear receptors, TR␣ 4 and TR␤, that act as ligand-dependent transcription factors by association, generally as heterodimers with retinoid X receptors, with thyroid hormone response elements located in regulatory regions of target genes (1). TRs can also modulate expression of genes that do not contain a hormone response element by modulating the activity of other transcription factors and signaling pathways (2), including activator protein-1 (AP-1)-, cyclic AMP-response element-, and nuclear factor-B (NF-B)-dependent pathways (3-7).Studies with knock-out (KO) mice for TRs obtained by homologous recombination have indicated that KO mice for ␣1 and ␤ TR isoforms have different phenotypes (8 -10) and that the double KO mice, surprisingly, survive (11), indicating that these receptors are not required for viability. Although these animals show extreme resistance to thyroid hormones, they exhibit a milder phenotype than hypothyroid mice, indicating divergent consequences for hormone versus receptor deficiency for some actions.Although the skin is a target tissue for thyroid hormone action, no studies on the skin phenotype in TR KO mice have been reported. TR␣ and TR␤ mRNAs are present in the skin (12-15), and these receptors can regulate either positively or negatively the expression of selected keratins in cultured cells (16 -19). Clinical evidence (19 -27) as well as studies in hypothyroid mice and rats (28 -30) also suggest that thyroid hormones could be involved in epidermal proliferation and differentiation, hair growth, and wound healing besides affecting the function of dermal fibroblasts. A question emerging from these studies is how to distinguish between effects due to altered thyroid hormone levels and effects due to expression of specific TR isoforms.The TR KO mice represent an excellent model for the analysis of the role of these receptors in the skin and its response to hyperproliferative stimuli. Topical application of 12-O-tetradecanolyphorbol-13-acetate (TPA) to mouse skin is a well known model for induction of skin hyperproliferation and also promotes a strong inflammatory reaction that activates multiple immunostimulatory pathways. The skin response to TPA is associated with activation of several intracellular pathways (e.g. mitogen-activated protein kinases (MAPKs), AKT, NF-B, STAT3, and AP-1) as well as an increase in the content of chemical mediators, such as cytokines, chemokines, vasoactive peptides, prostaglandins, leukotrienes, and nitric oxide among others (31)(32)(33)(34).In this work, we have investigated skin proliferation and inflammation, before and after TPA application, in mice lacking TR␣1, TR␤, or both genes, comparing these responses with those of hypothyroid animals to distinguish the specific contributions of receptor expression and activation. We found that TRs and thyroid hormones are required for skin homeostasis after TPA treatment and that both receptor genes contribute to

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Thyroid receptor: roles in cancer

Cited by 90 publications

References 66 publications

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

Thyroid hormone receptor β1 domains responsible for the antagonism with the ras oncogene: role of corepressors

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

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