Estrogen-Responsive Genes Overlap with Triiodothyronine-Responsive Genes in a Breast Carcinoma Cell Line

Figueiredo, Nancy Bueno; Cestari, Sílvia Helena; Conde, Sandro José; Luvizotto, Renata de Azevedo Melo; Síbio, Maria Teresa De; Perone, Denise; Katayama, Maria Lúcia Hirata; Carraro, Dirce Maria; Brentani, Helena; Brentani, Maria Mitzi; Nogueira, Célia Regina

doi:10.1155/2014/969404

Cited by 13 publications

(15 citation statements)

References 58 publications

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“…1 and 2). These results correlate with studies that demonstrated increased expression of a number of genes, such as amphiregulin (AREG) in MCF7 cells [40], leptin in adipocytes 3T3-L1 cells [41], and HIF1A in human fibroblast cells [39], upon treatment with T 3 . Taken together, these results show that T 3 affects the transcription of HIF1A and TGFA at both short periods of time.…”

Section: Discussionsupporting

confidence: 89%

Triiodothyronine (T3) induces HIF1A and TGFA expression in MCF7 cells by activating PI3K

et al. 2016

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High expression levels of hypoxia inducing factor 1 alpha are related to mammary carcinogenesis. In previous studies, we demonstrated that expression of transforming growth factor alpha increases upon treatment with triiodothyronine, but this expression does not occur in cellular models that do not express the estrogen receptor, or when cells are co-treated with the anti-estrogen, tamoxifen. The aim of this study was to determine the effect of the hormone triiodothyronine on the expression of the genes HIF1A and TGFA in the breast cancer cell line MCF7. The cell line was subjected to treatment with triiodothyronine at the supraphysiological dose of 10(-8)M for 10min, 30min, 1h, and 4h in the presence or absence of actinomycin D, the gene expression inhibitor, cycloheximide, the protein synthesis inhibitor, and LY294002, the phosphoinositide 3 kinase inhibitor. HIF1A and TGFA mRNA expression was analyzed by reverse transcription polymerase chain reaction. For data analysis, we used analysis of variance complemented by Tukey test and an adopted minimum of 5% significance. We found that HIF1A and TGFA expression increased in the presence of triiodothyronine at all times studied. HIF1A expression decreased in triiodothyronine-treated cells when gene transcription was also inhibited; however, TGFA expression decreased after 10 and 30min of treatment even when transcription was not inhibited. We found that activation of PI3K was necessary for triiodothyronine to modulate HIF1A and TGFA expression.

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Section: Discussionsupporting

confidence: 89%

Triiodothyronine (T3) induces HIF1A and TGFA expression in MCF7 cells by activating PI3K

et al. 2016

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“…These receptors act by binding specific DNA sequences called estrogen response elements (EREs) and thyroid response elements (TREs) within the regulatory regions of target genes [4,5] . Evidence of cross-talk between TH and E2 has been reported in past decades [6] in different experimental systems such as kidney [7] , neural [8,9] , thyroid [10] , and breast tumor [11][12][13] cell lines.…”

Section: Introductionmentioning

confidence: 99%

Impact of Thyroid Hormones on Estrogen Receptor α-Dependent Transcriptional Mechanisms in Ventromedial Hypothalamus and Preoptic Area

Faustino¹,

Gagnidze²,

Ortiga-Carvalho³

et al. 2015

Neuroendocrinology

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Elevated levels of thyroid hormones (TH) reduce estradiol (E2)-dependent female sexual behavior. E2 stimulates progesterone receptor (Pgr) and oxytocin receptor (Oxtr) within the ventromedial hypothalamus and preoptic area, critical hypothalamic nuclei for sexual and maternal behavior, respectively. Here, we investigated the impact of TH on E2-dependent transcriptional mechanisms in female mice. First, we observed that triiodothyronine (T₃) inhibited the E2 induction of Pgr and Oxtr. We hypothesized that differences in histone modifications and receptor recruitment could explain the influence of TH on E2-responsive Pgr and Oxtr expression. We observed that histone H3 acetylation (H3Ac) and methylation (H3K4me3) was gene and brain-region specific. We then analyzed the recruitment of estrogen receptor α (ERα) and TH receptor α (TRα) on the putative regulatory sequences of Pgr and Oxtr. Interestingly, T₃ inhibited E2-induced ERα binding to a specific Pgr enhancer site, whereas TRα binding was not affected, corroborating our theory that the competitive binding of TRα to an ERα binding site can inhibit ERα transactivation and the subsequent E2-responsive gene expression. On the Oxtr promoter, E2 and T₃ worked together to modulate ERα and TRα binding. Finally, the E2-dependent induction of cofactors was reduced by hypothyroidism and T₃. Thus, we determined that the Pgr and Oxtr promoter regions are responsive to E2 and that T₃ interferes with the E2 regulation of Pgr and Oxtr expression by altering the recruitment of receptors to DNA and changing the availability of cofactors. Collectively, our findings provide insights into molecular mechanisms of response to E2 and TH interactions controlling sex behavior in the hypothalamus.

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“…These studies have indicated that both T4 and T3 lead quickly (within hours) to an expression of an array of anti-apoptotic genes in tumor cells, thus supporting cancer development. 2,5,6,13,[15][16][17][18]22,[25][26][27][28][29] In a recent work from our group, we documented an inhibitory effect by thyroid hormones on the expression of six genes associated with tumor suppression (GDF-15, 30 IGFBP-6 13,31 ), apoptosis (Nix, PUMA 32 ), and cell cycle regulation (p21, p16 33,34 ), in ovarian cancer cell lines. 13 In the current study, we have extended our research to a panel The majority of the genes examined were downregulated by the hormones.…”

Section: Discussionmentioning

confidence: 99%

“…14 In this previous publication we have established that thyroid hormones play a regulatory role in the transcription of αvβ3 integrin subunits (monomers) and of certain additional genes involved in tumor suppression, cell cycle inhibition and mitochondrial apoptosis. 13 Given the fact that thyroid hormones effects on transcription can be initiated nongenomically through the thyroid-αvβ3 axis, 2,13,[15][16][17][18] we extended our analysis to fifteen cancer-relevant genes, whose expression is regulated by the nongenomically initiated actions of thyroid hormones. We also defined the involvement of the MAPK and PI3K signaling pathways to these effects of T4 and T3.…”

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confidence: 99%

Molecular insights into the transcriptional regulatory role of thyroid hormones in ovarian cancer

Shinderman-Maman

Weingarten

Moskovich

et al. 2017

Molecular Carcinogenesis

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The regulation of cancer-relevant genes by the thyroid hormones, 3, 5, 3′-Triiodo-Lthyronine (T3) and L-thyroxine (T4), was recently acknowledged. However, limited data exists on the hormonal effects on gene expression in ovarian cancer, a gynecological malignancy associated with a low cure rate. The expression of fifteen genes involved in DNA repair, cell cycle, apoptosis, and tumor suppression was evaluated in OVCAR-3 and A2780 cell lines, using real-time PCR following short incubation with T3 (1 nM) or T4 (100 nM). The thyroid hormones downregulated the expression of the majority of genes examined. Support for the involvement of the MAPK and PI3K in thyroid hormone-mediated gene expression was shown for a set of genes. FAS expression was inhibited in A2780 cells, while an unexpected induction was demonstrated in OVCAR-3 cells. An analogous effect on the protein levels of FAS receptor and its soluble form was demonstrated by Western blotting. We further established, using primer sets that discriminate between the different RNA isoforms, that the hormones increase the mRNA levels of both coding and non-coding FAS mRNAs. The prevalence of these isoforms, using The Cancer Genome Atlas (TCGA) analysis, was significantly more abundant in 17 cancer types, including ovarian cancer, compared to normal tissues. Our results highlight the role of thyroid hormones in the expression of cancer-relevant-genes in ovarian cancer and provide an important insight into the pathways by which mitogenic and anti-apoptotic effects are exerted. This integrin contains an Arg-Gly-Asp (RGD) recognition site that binds extra cellular matrix (ECM) proteins containing this sequence. At close proximity to the RGD recognition site, a thyroid hormone receptor was described. 1,2 The receptor is complex and includes a site for T3 and a second site for T3 and for L-thyroxine (T4), 3 the principal secretory product of the thyroid gland. Physiological levels of T4 activate the thyroid hormone receptor on αvβ3, whereas supraphysiologic concentrations of T3 are required to achieve stimulation at this Molecular Carcinogenesis. 2018;57:97-105.wileyonlinelibrary.com/journal/mc

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Estrogen-Responsive Genes Overlap with Triiodothyronine-Responsive Genes in a Breast Carcinoma Cell Line

Cited by 13 publications

References 58 publications

Triiodothyronine (T3) induces HIF1A and TGFA expression in MCF7 cells by activating PI3K

Triiodothyronine (T3) induces HIF1A and TGFA expression in MCF7 cells by activating PI3K

Impact of Thyroid Hormones on Estrogen Receptor α-Dependent Transcriptional Mechanisms in Ventromedial Hypothalamus and Preoptic Area

Molecular insights into the transcriptional regulatory role of thyroid hormones in ovarian cancer

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