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

Int J Oncol. 2010 May;36(5):1067-80. doi: 10.3892/ijo_00000588.

Abstract

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 alpha and beta (ER), the effects of estradiol (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 ERalpha and ERbeta proteins with cytoplasmic localization that was unaffected by E2. ICI 182,780 (Fulvestrant, an ER antagonist), and inhibitors of non-genomic E2-activated MAPK and PI3K signaling blocked E2-induced cell proliferation. SERMs acted in a cell line-specific manner. No E2-induced estrogen response element (ERE)-driven reporter activity was observed in transiently transfected thyroid cancer cells. However, E2 increased transcription of established endogenous E2-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, E2 did not increase progesterone receptor expression in the thyroid cancer cell lines. E2 stimulated phosphorylation of ERK1/2 in KAT5 and WRO cells and siERalpha or siERbeta inhibited E2-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 E2-mediated thyroid cancer cell proliferation involves ERalpha and ERbeta transcriptional and non-genomic signaling events.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Estradiol / analogs & derivatives
  • Estradiol / metabolism
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / metabolism*
  • Fulvestrant
  • Humans
  • Phosphorylation
  • RNA, Small Interfering / metabolism
  • Raloxifene Hydrochloride / pharmacology
  • Signal Transduction
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Thyroid Neoplasms / metabolism*

Substances

  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • RNA, Small Interfering
  • Tamoxifen
  • afimoxifene
  • Fulvestrant
  • Raloxifene Hydrochloride
  • Estradiol