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Glucocorticoids Antagonize Estrogens by Glucocorticoid Receptor–Mediated Activation of Estrogen Sulfotransferase

¹ Center for Pharmacogenetics and Department of Pharmaceutical Sciences, ² University of Pittsburgh Cancer Institute and Department of Pathology, and ³ Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania; ⁴ Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; and ⁵ Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Wen Xie, Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261. Phone: 412-648-9941; Fax: 412-648-1664; E-mail: wex6{at}pitt.edu.

Key Words: gene regulation • hormone metabolism • nuclear receptor

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. [Cancer Res 2008;68(18):7386–93]