Estrogen regulation of the glucuronidation enzyme UGT2B15 in estrogen receptor-positive breast cancer cells

William R. Harrington, Surojeet Sengupta, Benita S Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

Estrogens and androgens influence many properties of breast cancer cells; hence, regulation of local estrogen and androgen levels by enzymes involved in steroid hormone biosynthesis and metabolism would impact signaling by these hormones in breast cancer cells. In this study, we show that the UDP-glucuronosyltransferase (UGT) enzyme UGT2B15, a member of the UGT family of phase II enzymes involved in the glucuronidation of steroids and xenobiotics, is a novel, estrogen-regulated gene in estrogen receptor (ER)-positive human breast cancer cells (MCF-7, BT474, T47D, and ZR-75).UGT2B15 is the only UGT2B enzyme up-regulated by estrogen, and marked estradiol stimulation of UGT2B15 mRNA levels is observed, in a time- and dose-dependent manner. UGT2B15 stimulation by estradiol is blocked by the antiestrogen ICI182,780, but not by the translational inhibitor cycloheximide, indicating that UGT2B15 is likely a primary transcriptional response mediated through the ER. UGT2B15 up-regulation is also evoked by other estrogens (propylpyrazoletriol, genistein) and by the androgen 5α-dihydrotestosterone working through the ER, but not by other steroid hormone receptor ligands. Western blot and immunocytochemical analyses with several UGT2B-specific antibodies we have designed and steroid glucuronidation assays indicate a large increase in both cellular UGT2B15 protein and enzyme activity after estrogen treatment. Due to the important role of UGT enzymes in forming conjugates between steroids and glucuronic acid, thereby inactivating them and targeting them for removal, the estrogen-induced up-regulation of UGT2B15 might have a significant moderating effect on estrogen and androgen concentrations, thereby reducing their signaling in breast cancer cells.

Original languageEnglish (US)
Pages (from-to)3843-3850
Number of pages8
JournalEndocrinology
Volume147
Issue number8
DOIs
StatePublished - Jul 24 2006

Fingerprint

Estrogen Receptors
Estrogens
Breast Neoplasms
Enzymes
Glucuronosyltransferase
Androgens
Steroids
Hormones
Estradiol
Up-Regulation
Glucuronic Acid
Estrogen Receptor Modulators
Genistein
Dihydrotestosterone
Steroid Receptors
MCF-7 Cells
Xenobiotics
Cycloheximide
Western Blotting
Ligands

ASJC Scopus subject areas

  • Endocrinology

Cite this

Estrogen regulation of the glucuronidation enzyme UGT2B15 in estrogen receptor-positive breast cancer cells. / Harrington, William R.; Sengupta, Surojeet; Katzenellenbogen, Benita S.

In: Endocrinology, Vol. 147, No. 8, 24.07.2006, p. 3843-3850.

Research output: Contribution to journalArticle

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