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

Abstract

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 dem-onstrated 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 signif-icant increase in expression levels in response to 17␤-estradiol. Stim-ulation of benign and malignant thyroid cells with 17␤-estradiol re-sulted 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 an-tagonist, prevented the effects of 17␤-estradiol. In addition, 17␤-estradiol was found to modulate activation of mitogen-activated pro-tein (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 thy-roid 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 17␤-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.