Metastatic Phenotype Is Regulated by Estrogen in Thyroid Cells (original) (raw)
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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.
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.
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 and estrogen receptors in thyroid carcinomas
Journal of Surgical Oncology, 1991
Thyroid tissues, composed of normal thyroid (10 cases), Graves' thyroid (4), and papillary carcinoma (lo), were measured for the presence of receptors for estrogen (ER) using an enzyme-immunoassay method. The mean value of ER in papillary carcinoma tissues (4.0 ? 3.6 fmol/mg protein) was higher than that in normal thyroid tissues (0.8 -+ 0.4 fmol/mg protein) or that in Graves' thyroids (2.6 ? 0.9 fmol/mg protein). In 10 papillary carcinomas, 3 were from male patients and 7 were from females. The mean value of ER in the tumors from male patients (7.2 2 5.1 fmol/mg protein) was higher than that from female patients (2.6 -+ 1.7 fmol/mg protein).
Estrogen and thyroid cancer is a stem affair: A preliminary study
Biomedicine & Pharmacotherapy, 2017
Gender influences Papillary Thyroid Cancer (PTC) with an incidence of 3:1 when comparing women to men with different aggressiveness. This gender discrepancy suggests some role of sex hormones in favoring the malignant progression of thyroid tissue to cancer. Estrogens are known to promote Stem Cell self-renewal and, therefore, may be involved in tumor initiation. The goals of these studies are to investigate the underlying causes of gender differences in PTC by studying the specific role of estrogens on tumor cells and their involvement within the Cancer Stem Cell (CSC) compartment. Exposure to 1 nmol l −1 Estradiol for 24 h promotes growth and maintenance of PTC Stem Cells, while inducing dose-dependent cellular proliferation and differentiation following Estradiol administration. Whereas mimicking a condition of hormonal imbalance led to an opposite phenotype compared to a continuous treatment. In vivo we find that Estradiol promotes motility and tumorigenicity of CSCs. Estradiol-treated mice inoculated with Thyroid Cancer Stem Cell-enriched cells developed larger tumor masses than control mice. Furthermore, Estradiol-pretreated Cancer Stem cells migrated to distant organs, while untreated cells remained circumscribed. We also find that the biological response elicited by estrogens on Papillary Thyroid Cancer in women differed from men in pathways mediated. This could explain the gender imbalance in tumor incidence and development and could be useful to develop gender specific treatment of (PTC).
Estrogen and thyroid cancer is a stem affair: A preliminary study HHS Public Access
Gender influences Papillary Thyroid Cancer (PTC) with an incidence of 3:1 when comparing women to men with different aggressiveness. This gender discrepancy suggests some role of sex hormones in favoring the malignant progression of thyroid tissue to cancer. Estrogens are known to promote Stem Cell self-renewal and, therefore, may be involved in tumor initiation. The goals of these studies are to investigate the underlying causes of gender differences in PTC by studying the specific role of estrogens on tumor cells and their involvement within the Cancer Stem Cell (CSC) compartment. Exposure to 1 nmol l −1 Estradiol for 24 h promotes growth and maintenance of PTC Stem Cells, while inducing dose-dependent cellular proliferation and differentiation following Estradiol administration. Whereas mimicking a condition of hormonal imbalance led to an opposite phenotype compared to a continuous treatment. In vivo we find that Estradiol promotes motility and tumorigenicity of CSCs. Estradiol-treated mice inoculated with Thyroid Cancer Stem Cell-enriched cells developed larger tumor masses than control mice. Furthermore, Estradiol-pretreated Cancer Stem cells migrated to distant organs, while untreated cells remained circumscribed. We also find that the biological response elicited by estrogens on Papillary Thyroid Cancer in women differed from men in pathways mediated. This could explain the gender imbalance in tumor incidence and development and could be useful to develop gender specific treatment of (PTC).
Endocrine Related Cancer, 2012
Estrogen receptor (ER) and androgen receptor (AR) may be expressed in thyroid tumors, but their prognostic role is controversial. We investigated whether ER and AR expressions could confer a more aggressive phenotype to thyroid tumors. We enrolled 91 patients (13 males and 78 females, mean age 49.3±14.8 years) bearing small (T1 in the 2006 TNM system) differentiated thyroid cancers (DTC). Thirty-eight tumors were incidental histological findings. Using immunohistochemistry, we evaluated ERα, ERβ, and AR expressions in tumors and in its correspondent extra-tumor parenchyma. In tumors, 13 (16.7%) women and one (7.7%) man expressed ERα; 42 (53.8%) women and six (46%) men expressed ERβ; and 16 (20.5%) women and three (23.1%) men expressed AR. In normal thyroid parenchymas, ERβ was expressed in 52 (66.7%) women and nine (69.2%) men, ERα in three (3.8%) women, and AR in 13 (16.7%) women. Compared with normal thyroid parenchyma, tumors gained ERα and lost ERβ expressions. Incidental cancer...
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 ...