Glucocorticoids antagonize estrogens by glucocorticoid receptor-mediated activation of estrogen sulfotransferase

Haibiao Gong, Michael J. Jarzynka, Timothy J. Cole, Hoon Lee Jung, Taira Wada, Bin Zhang, Jie Gao, Wen Chao Song, Donald B. DeFranco, Shi Yuan Cheng, Wen Xie*

*Corresponding author for this work

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

Glucocorticoids and estrogens are two classes of steroid hormones that have essential but distinct physiologic functions. Estrogens also represent a risk factor for breast cancer. It has been suggested that glucocorticoids can attenuate estrogen responses, but the mechanism by which glucocorticoids inhibit estrogenic activity is unknown. In this study, we show that activation of glucocorticoid receptor (GR) by dexamethasone (DEX) induced the expression and activity of estrogen sulfotransferase (SULT1E1 or EST), an enzyme important for the metabolic deactivation of estrogens, because sulfonated estrogens fail to activate the estrogen receptor. Treatment with DEX lowered circulating estrogens, compromised uterine estrogen responses, and inhibited estrogen-dependent breast cancer growth in vitro and in a xenograft model. We further showed that the mouse and human SULT1E1 genes are transcriptional targets of GR and deletion of Sult1e1/Est in mice abolished the DEX effect on estrogen responses. These findings have revealed a novel nuclear receptor-mediated and metabolism-based mechanism of estrogen deprivation, which may have implications in therapeutic development for breast cancers. Because glucocorticoids and estrogens are widely prescribed drugs, our results also urge caution in avoiding glucocorticoid-estrogen interactions in patients.

Original languageEnglish (US)
Pages (from-to)7386-7393
Number of pages8
JournalCancer Research
Volume68
Issue number18
DOIs
StatePublished - Sep 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Gong, H., Jarzynka, M. J., Cole, T. J., Jung, H. L., Wada, T., Zhang, B., Gao, J., Song, W. C., DeFranco, D. B., Cheng, S. Y., & Xie, W. (2008). Glucocorticoids antagonize estrogens by glucocorticoid receptor-mediated activation of estrogen sulfotransferase. Cancer Research, 68(18), 7386-7393. https://doi.org/10.1158/0008-5472.CAN-08-1545