Estrogen promotes growth of human thyroid tumor cells by different molecular mechanisms.
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 17beta-estradiol was demonstrated in FRTL-5 rat thyroid cells. In this work the presence of estrogen receptors alpha and beta 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 17beta-estradiol. Stimulation of benign and malignant thyroid cells with 17beta-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 17beta-estradiol was delayed. ICI 182780, a pure estrogen antagonist, prevented the effects of 17beta-estradiol. In addition, 17beta-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 17beta-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 17beta-estradiol and MAP kinase kinase 1 inhibitor, PD 098059, prevented the accumulation of cyclin D1 and estrogen-mediated mitogenesis. Our data indicate that 17beta-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.
Division of Endocrinology, Department of Medicine, St. Hedwig Hospital, 10115 Berlin, Germany.
D
D
Manole
B
B
Schildknecht
B
B
Gosnell
E
E
Adams
M
M
Derwahl
D000230:Adenocarcinoma / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects*; D019938:Cyclin D1 / Q000032:analysis; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006042:Goiter / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011960:Receptors, Estrogen / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013961:Thyroid Gland / Q000737:chemistry; D013964:Thyroid Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D019938:Cyclin D1; D004958:Estradiol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases