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

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Harrington WR, Sengupta S, Katzenellenbogen BS

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

Endocrinology. 2006 Aug;147(8):3843-50. Epub 2006 May 11.

PubMed ID

16690804 [ View in PubMed

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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 5alpha-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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Estradiol	UDP-glucuronosyltransferase 2B15	Protein	Humans	Unknown	Inducer	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Stanolone	Illicit Investigational	UGT2B15	7366	upregulated	Dihydrotestosterone results in increased expression of UGT2B15 mRNA	4q13.2
Estradiol	Approved Investigational Vet Approved	UGT2B15	7366	upregulated	Estradiol results in increased expression of UGT2B15 mRNA	4q13.2
Genistein	Investigational	UGT2B15	7366	upregulated	Genistein results in increased expression of UGT2B15 mRNA	4q13.2