Estradiol-induced proliferation of papillary and follicular thyroid cancer cells is mediated by estrogen receptors α and β

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 a and B (ER). the effects of estrathol (E2), 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 alpha and ER beta 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 clement (ERE)-driven reporter activity was observed in transiently transfected thyroid cancer cells. However, E, 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, did not increase progesterone receptor expression in the thyroid cancer cell lines. E2 stimulated phosphorylation of ERK1/2 in KAT5 and WRO cells and siER alpha or siER beta 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-mechated thyroid cancer cell proliferation involves ER alpha and ER beta transcriptional and non-genomic signaling events.