Oestrogen mediates the growth of human thyroid carcinoma cells via an oestrogen receptor – ERK pathway (original) (raw)
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International Journal of Oncology, 2010
Premenopausal women are at highest risk for papillary and follicular thyroid carcinoma, implicating a role for estrogens in thyroid cancer. The expression of estrogen receptors • and ß (ER), the effects of estradiol (E 2), selective estrogen receptor modulators (SERMs) 4-hydroxytamoxifen and raloxifene, and ER subtype selective agonists were examined in NPA87 and KAT5 papillary and WRO follicular thyroid carcinoma cell lines. All three thyroid cancer cell lines expressed full-length ER• and ERß proteins with cytoplasmic localization that was unaffected by E 2. ICI 182,780 (Fulvestrant, an ER antagonist), and inhibitors of non-genomic E 2-activated MAPK and PI3K signaling blocked E 2-induced cell proliferation. SERMs acted in a cell line-specific manner. No E 2-induced estrogen response element (ERE)-driven reporter activity was observed in transiently transfected thyroid cancer cells. However, E 2 increased transcription of established endogenous E 2-target genes, i.e., cathepsin D in WRO and cyclin D1 in both KAT5 and WRO cells in an ER-dependent manner as validated by inhibitor and siRNA experiments. In contrast, E 2 did not increase progesterone receptor expression in the thyroid cancer cell lines. E 2 stimulated phosphorylation of ERK1/2 in KAT5 and WRO cells and siER• or siERß inhibited E 2-induced ERK phosphorylation. Expression of the putative membrane estrogen receptor GPR30 was detected in WRO, but not NPA87 or KAT5 cells. GPR30 expression was lower in WRO than MCF-7 human breast cancer cells. Overall, these findings suggest E 2-mediated thyroid cancer cell proliferation involves ER• and ERß transcriptional and non-genomic signaling events.
Estrogen Promotes Growth of Human Thyroid Tumor Cells by Different Molecular Mechanisms 1
The Journal of Clinical Endocrinology & Metabolism, 2001
Thyroid tumors are about 3 times more frequent in females than in males. Epidemiological studies suggest that the use of estrogens may contribute to the pathogenesis of thyroid tumors. In a very recent study a direct growth stimulatory effect of 17-estradiol was demonstrated in FRTL-5 rat thyroid cells. In this work the presence of estrogen receptors ␣ and  in thyroid cells derived from human goiter nodules and in human thyroid carcinoma cell line HTC-TSHr was demonstrated. There was no difference between the expression levels of estrogen receptor ␣ in males and females, but there was a significant increase in expression levels in response to 17-estradiol. Stimulation of benign and malignant thyroid cells with 17-estradiol resulted in an increased proliferation rate and an enhanced expression of cyclin D1 protein, which plays a key role in the regulation of G 1 /S transition in the cell cycle. In malignant tumor cells maximal cyclin D1 expression was observed after 3 h, whereas in benign cells the effect of 17-estradiol was delayed. ICI 182780, a pure estrogen antagonist, prevented the effects of 17-estradiol. In addition, 17estradiol was found to modulate activation of mitogen-activated protein (MAP) kinase, whose activity is mainly regulated by growth factors in thyroid carcinoma cells. In response to 17-estradiol, both MAP kinase isozymes, extracellular signal-regulated protein kinases 1 and 2, were strongly phosphorylated in benign and malignant thyroid cells. Treatment of the cells with 17-estradiol and MAP kinase kinase 1 inhibitor, PD 098059, prevented the accumulation of cyclin D1 and estrogen-mediated mitogenesis. Our data indicate that 17estradiol is a potent mitogen for benign and malignant thyroid tumor cells and that it exerts a growth-promoting effect not only by binding to nuclear estrogen receptors, but also by activation of the MAP kinase pathway.
Estrogen promotes growth of human thyroid tumor cells by different molecular mechanisms
Journal of Clinical …, 2001
Thyroid tumors are about 3 times more frequent in females than in males. Epidemiological studies suggest that the use of estrogens may contribute to the pathogenesis of thyroid tumors. In a very recent study a direct growth stimulatory effect of 17-estradiol was demonstrated in FRTL-5 rat thyroid cells. In this work the presence of estrogen receptors ␣ and  in thyroid cells derived from human goiter nodules and in human thyroid carcinoma cell line HTC-TSHr was demonstrated. There was no difference between the expression levels of estrogen receptor ␣ in males and females, but there was a significant increase in expression levels in response to 17-estradiol. Stimulation of benign and malignant thyroid cells with 17-estradiol resulted in an increased proliferation rate and an enhanced expression of cyclin D1 protein, which plays a key role in the regulation of G 1 /S transition in the cell cycle. In malignant tumor cells maximal cyclin D1 expression was observed after 3 h, whereas in benign cells the effect of 17-estradiol was delayed. ICI 182780, a pure estrogen antagonist, prevented the effects of 17-estradiol. In addition, 17estradiol was found to modulate activation of mitogen-activated protein (MAP) kinase, whose activity is mainly regulated by growth factors in thyroid carcinoma cells. In response to 17-estradiol, both MAP kinase isozymes, extracellular signal-regulated protein kinases 1 and 2, were strongly phosphorylated in benign and malignant thyroid cells. Treatment of the cells with 17-estradiol and MAP kinase kinase 1 inhibitor, PD 098059, prevented the accumulation of cyclin D1 and estrogen-mediated mitogenesis. Our data indicate that 17estradiol is a potent mitogen for benign and malignant thyroid tumor cells and that it exerts a growth-promoting effect not only by binding to nuclear estrogen receptors, but also by activation of the MAP kinase pathway.
International Journal of Molecular Sciences, 2022
Papillary thyroid carcinomas (PTC), which is derived from thyroid follicular cells, is the most commonly differentiated thyroid cancer with sex disparity. However, the role of estrogen receptors (ERs) in the pathogenesis of PTC remains unclear. The present study aimed to determine the association of ER mRNA expression levels with clinicopathologic features in PTC. To that aim, the mRNA levels of ESR1 (ERα66), ESR1 (ERα36), ESR2, and G-protein-coupled estrogen receptor 1 (GPER1) in snap-frozen tissue samples from PTCs and adjacent normal thyroid tissues were determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the correlation between ER mRNA expression levels and clinicopathologic features was analyzed. The expression of ERα66, ERα36, ERβ, and GPER1 was lower in PTC specimens than in adjacent normal thyroid tissues. Moreover, low GPER1 expression was associated with extrathyroidal extension. There was no obvious difference in expression of ERs ...
Cancer, 2014
BACKGROUND: Estrogen receptor (ER) and peroxisome proliferator-activated receptor gamma (PPARg) are associated with thyroid tumorigenesis and treatment. However, the interaction between them has not been studied. METHODS: The impact of ER overexpression or down-expression by DNA/small interfering RNA (siRNA) transfection, ERa agonists, and the ERb agonist diarylpropiolnitrile (DPN) on PPARg expression/activity was examined in papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC) cells. The effects of PPARg modulation by rosiglitazone (RTZ), a PPARg ligand, and of PPARg siRNA on ER expression were determined. Cellular functions reflected by cell proliferation and migration were assayed. Apoptosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick-end labeling, and apoptotic-related proteins were evaluated by Western blot analysis. RESULTS: PPARg protein and activity were reduced by the over-expression of either ERa or ERb, whereas repression of ERa or ERb increased PPARg expression. The administration of RTZ counteracted the effects of ER and also reduced their expression, particularly in PTC cells. Moreover, knockdown of PPARg increased ER expression and activity. Functionally, ERa activation offset the inhibitory effect of PPARg on cellular functions, but ERb activation aggregated it and induced apoptosis, particularly in PTC cells. Finally, the interaction between ERb and PPARg enhanced the expression of proapoptotic molecules, such as caspase-3 and apoptosis-inducing factor. CONCLUSIONS: This study provides evidence supporting a cross-talk between ER and PPARg. The reciprocal interaction between PPARg and ERb significantly inhibits the proliferation and migration of thyroid cancer cells, providing a new therapeutic strategy against thyroid cancer. Cancer 2014;120:142-53.
Immunohistochemical expression of ER-α and PR in papillary thyroid carcinoma
ecancermedicalscience, 2017
Papillary thyroid carcinoma (PTC) is the most common thyroid cancer with multiple risk factors including exposure to ionising radiation. Oestrogens contribute to papillary carcinoma development by promoting cell proliferation and invasion of mutated epithelial follicular cells. The present study aimed to assess ER-α and PR expression in PTC and to correlate their expression with the clinicopathological parameters in this cancer. This study included 62 primary and six metastatic papillary thyroid carcinoma cases. Nineteen and 38.7% of primary PTC cases showed positive nuclear expression for ER and PR, respectively. Metastatic cases showed 66.7% positive ER expression and all were negative for PR. Oestrogen receptor expression showed significant higher positivity in metastatic compared to primary PTC (p = 0.02) and it was significantly associated with primary PTC associated with thyroiditis (p = .002). Progesterone receptor expression was significantly associated with old age in primary PTC (p = .003) and it showed significant coparallel expression with ER (p = .000). Oestrogen and progesterone receptors expressed in papillary thyroid carcinoma opening the door for further studies to verify if those patients could benefit from hormonal therapy. Oestrogen receptor seems to have a role in metastatic process of PTC as malignant cells express it in metastatic more than primary site. The presence of lymphocytes in the stroma may promote ER expression in adjacent PTC, necessitating further studies on PTC cases associated with Hashimoto thyroiditis to verify this assumed relationship.
The Isoforms of Estrogen Receptor Alpha and Beta in Thyroid Cancer
Frontiers in Oncology
The incidence of thyroid cancer was predominant in women, indicating that the sex hormone may have a role in thyroid cancer development. Generally, the sex hormone exerts its function by binding to the correspondent nuclear receptors. Therefore, aberrant of these receptors may be involved in the development of thyroid cancer. Estrogen receptor alpha (ERα) and beta (ERβ), two main estrogen receptors, have been reported to have an important role in the pathogenesis of thyroid cancer. When the ERα and ERβ genes undergo the alternative RNA splicing, some ERα and ERβ isoforms with incomplete functional domains may be formed. To date, several isoforms of ERα and ERβ have been identified. However, their expression and roles in thyroid cancer are far from clear. In this review, we summarized the expressions and roles of ERα and ERβ isoforms in thyroid cancer, aiming to provide the perspective of modulating the alternative RNA splicing of ERα and ERβ against thyroid cancer.
Metastatic Phenotype Is Regulated by Estrogen in Thyroid Cells
Thyroid, 2010
Background: Over 200 million people worldwide are affected by thyroid proliferative diseases, including cancer, adenoma, and goiter, annually. The incidences of thyroid malignancies are three to four times higher in women, suggesting the possible involvement of estrogen. Based on this observed sex bias, we hypothesize that estrogen modulates the growth and metastatic propensity of thyroid cancer cells. Methods: In this study, two thyroid cell lines (Nthy-ori 3-1 and BCPAP) were evaluated for the presence of estrogen receptor (ER) by Western blot analysis and estrogen responsiveness by using a cell proliferation assay. In addition, the effect of estradiol (E 2 ) on modulation of metastatic phenotype was determined by using in vitro adhesion, migration, and invasion assays. Results: Thyroid cells expressed a functionally active ER-a and ER-b as evidenced by 50-150% enhancement of proliferation in the presence of E 2 . E 2 also enhanced adhesion, migration, and invasion of thyroid cells in an in vitro experimental model system that, based on our results, is modulated by b-catenin. Conclusion: Our data provide evidence that the higher incidence of thyroid cancer in women is potentially attributed to the presence of a functional ER that participates in cellular processes contributing to enhanced mitogenic, migratory, and invasive properties of thyroid cells. These findings will enable and foster the possible development of antiestrogenic therapy targeting invasion and migration, thus affecting metastatic propensity.