Estrogen promotes growth of human thyroid tumor cells by different molecular mechanisms (original) (raw)
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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.
Growth inhibitory effects of thyroid hormones on androgen-dependent mammary tumor cells
Journal of Steroid Biochemistry, 1981
The role played by thyroid hormones in breast cancer onset and progression both in animals and in humans has not yet been clearly defined. Moreover interactions between thyroid hormones and steroids are of special interest with respect to the control of breast cancer growth. which is known to be affected by several hormonal stimuli. The proliferative effects of thyroid hormones and their possible interactions with androgens were investigated in the androgen-de~ndent (+A ceils) and autonomous (-A ceils) variant of the Shionogi ii5 mouse mammary carcinoma. The presence of physiological concentrations of triiodothyronine (Ts) in the S 115 culture medium inhibits ceil growth in a dose-dependent fashion both in + A and -A ceils. The inhibition produced by T, is not influenced by androgens suggesting that the growth regulatory mechanisms of these hormones are distinct and noninteracting. S 115 cells contain a limited number of high affinity nuclear T, receptors. The correspondence between binding capacity of the nuclear receptor and biological activity of various thyroid hormone anaiogues suggests that the proliferative effect is mediated via receptor mechanism. Finally. ceils maintained for two weeks in medium deprived of thyroid hormones lose their responsiveness to T, through a still unknown process.
Endocrine Pathology, 2001
Differential effects of testosterone and estradiol on the proliferation of human thyroid papillary (NPA-87-1) and follicular (WRO-82-1) carcinoma cell lines were assessed by [ 3 H]-thymidine incorporation and the cell number. Cells (2.5 × 10 5) plated in 24-well culture plates in 400 µL RPMI-1640 medium/well, under 5% CO 2 and 95% air, at 37°C were exposed to linearly increasing concentrations of human thyroid-stimulating hormone (hTSH) (1.25-640 ng/mL), testosterone (1.25-640 ng/mL), or estradiol (1.25-640 pg/mL) for 24 h. Testosterone and estradiol increased the proliferation of NPA cell line in a dosedependent manner; flutamide (an anti-androgen) and tamoxifen (an anti-estrogen) (10-8 , 10-7 , 10-6 , and 10-5 mol/L) effectively inhibited the testosterone and estradiol-induced cell proliferation, respectively. While flutamide inhibited the stimulatory effect of testosterone on the WRO cell line, tamoxifen augmented the inhibitory effect of estradiol. TSH did not have any effect on the proliferation of NPA or WRO cell lines, and testosterone-estradiol had no impact on TSH binding to these cells. N-ethylmalemide (5α-reductase inhibitor) (10-8-10-5 mol/L) did not modulate basal and testosterone-induced cell proliferation, indicating the direct effect of testosterone without getting converted into dihydrotestosterone (DHT). Both the cell lines tested positive for androgen and estrogen receptors and were up-regulated by the respective ligands. It is concluded that testosterone and estradiol modify the proliferation of thyroid cancer cells through homologous up-regulation of their own receptors, which is independent of TSH, and their effects may vary according to the cell type.
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.
Influence of thyroid hormone receptors on breast cancer cell proliferation
Annals of Oncology, 2005
Background: The involvement of thyroid hormones in the development and differentiation of normal breast tissue has been established. However, the association between breast cancer and these hormones is controversial. Therefore, the objective of the present study was to determine the protein expression pattern of thyroid hormone receptors in different human breast pathologies and to evaluate their possible relationship with cellular proliferation.
Cell Proliferation, 2007
Objectives : Although thyroid cancer occurs much more frequently in females, the role of sex hormones in thyroid carcinogenesis is unknown. In this study, it has been investigated how 17 β-oestradiol (E2) influenced proliferation and growth of thyroid cancer cells. Materials and Methods : Cell proliferation and its related molecules were examined in thyroid papillary carcinoma cells (KAT5), follicular thyroid carcinoma cells (FRO) and anaplastic carcinoma cells (ARO). Levels of oestrogen receptor (ER) α and β were regulated by their agonists (PPT and DPN), antagonists and siRNA. Results : E2 promoted cell proliferation. Such an effect was positively related to ER α but negatively to ER β ; PPT enhanced cell proliferation while DPN inhibited it. PPT increased Bcl-2 expression while DPN decreased it. DPN also elevated Bax expression. PPT elevated the level of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), suggesting a positive role of ERK1/2 in E2-induced cell proliferation. Knockdown of ER α significantly attenuated E2-mediated Bcl-2 and pERK1/2 expression. In contrast, knockdown of ER β markedly enhanced them. Conclusions : Oestrogen stimulates proliferation of thyroid cancer cells, associated with increase in Bcl-2 and decrease in Bax levels in an ERK1/2-related pathway. Imbalance between ER α and ER β may contribute to thyroid carcinogenesis.
Molecular Endocrinology, 2004
We have addressed the question of rapid, nongenomic mechanisms that may be involved in the mitogenic action of estrogens in hormonedependent breast cancer cells. In quiescent, estrogen-deprived MCF-7 cells, estradiol did not induce a rapid activation of either the MAPK/ ERK or phosphatidylinositol-3 kinase (PI-3K)/Akt pathway, whereas the entry into the cell cycle was documented by the successive inductions of cyclin D1 expression, hyperphosphorylation of the retinoblastoma protein (Rb), activity of the promoter of the cyclin A gene, and DNA synthesis. However, pharmacological inhibitors of the src family kinases, 4-amino-5-(4-methylphenyl)-