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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 3 1072-1077
Copyright © 2001 by The Endocrine Society

Original Studies

Estrogen Promotes Growth of Human Thyroid Tumor Cells by Different Molecular Mechanisms1

Diana Manole, Beatrice Schildknecht, Bernadett Gosnell, Eric Adams and Michael Derwahl

Division of Endocrinology, Department of Medicine, St. Hedwig Hospital, 10115 Berlin, Germany; Humboldt University Berlin, Berlin, Germany; and Faculty of Biology, Aston University (E.A.), B4 7ET Birmingham, United Kingdom

Address all correspondence and requests for reprints to: Dr. Michael Derwahl, St. Hedwig Hospital, Grosse Hamburger Strasse 5-11, 10115 Berlin, Germany. E-mail: m.derwahl{at}alexius.de

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 17ß-estradiol was demonstrated in FRTL-5 rat thyroid cells. In this work the presence of estrogen receptors {alpha} and ß 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 {alpha} in males and females, but there was a significant increase in expression levels in response to 17ß-estradiol. Stimulation of benign and malignant thyroid cells with 17ß-estradiol resulted in an increased proliferation rate and an enhanced expression of cyclin D1 protein, which plays a key role in the regulation of G1/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 17ß-estradiol was delayed. ICI 182780, a pure estrogen antagonist, prevented the effects of 17ß-estradiol. In addition, 17ß-estradiol 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 17ß-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 17ß-estradiol and MAP kinase kinase 1 inhibitor, PD 098059, prevented the accumulation of cyclin D1 and estrogen-mediated mitogenesis. Our data indicate that 17ß-estradiol 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.




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