Journal Article

Prostaglandin E<sub>2</sub> Induces CYP1B1 Expression <i>via</i> Ligand-Independent Activation of the ERα Pathway in Human Breast Cancer Cells

Eun H. Han, Hyung G. Kim, Young P. Hwang, Gye Yong Song and Hye G. Jeong

in Toxicological Sciences

Volume 114, issue 2, pages 204-216
Published in print April 2010 | ISSN: 1096-6080
Published online January 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq013
Prostaglandin E2 Induces CYP1B1 Expression via Ligand-Independent Activation of the ERα Pathway in Human Breast Cancer Cells

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Breast cancer is a major cause of death worldwide. Human cytochrome P450 (CYP) 1B1 is a key enzyme in the metabolism of 17β-estradiol, and CYP1B1-metabolized 4-hydroxyestradiol is a marker for breast cancer. Furthermore, overexpression of cyclooxygenase-2 (COX-2), which produces prostaglandin E2 (PGE2), has been detected in invasive breast carcinomas. However, the interaction between PGE2 and CYP1B1 expression in human breast cancer is unclear. Here, we investigated the effect of PGE2 on CYP1B1 expression and its mechanism in breast cancer cells. PGE2 significantly increased CYP1B1 protein and messenger RNA expression and dose dependently enhanced CYP1B1 promoter activity in human breast cancer MCF-7 cells. Transient transfection with human CYP1B1 (hCYP1B1) deletion promoter constructs and cotreatment with inhibitors revealed that the estrogen response element contributed to the effects of PGE2. CYP1B1 expression was not affected by PGE2 in estrogen receptor (ER) α-negative MDA-MB-231 breast cancer cells or in ERα/β-negative MCF-10A normal breast cells, and protein expression of ERα and ERβ was not affected by PGE2 treatment in MCF-7 cells. However, PGE2 rapidly induced phosphorylation of ERα at serine residues 118, 167, and 305, suggesting that PGE2 activates ERα in a ligand-independent manner. PGE2 also increased phosphorylation of extracellular signal-regulated kinase (ERK), Akt, and protein kinase A (PKA). Finally, a COX-2 inhibitor inhibited PGE2-induced CYP1B1 expression, and COX-2 overexpression increased CYP1B1 expression. Our results indicate that PGE2-induced CYP1B1 expression is mediated by ligand-independent activation of the ERα pathway as a result of the activation of ERK, Akt, and PKA in breast cancer cells.

Keywords: prostaglandin E2; CYP1B1; ERα; cyclooxygenase-2

Journal Article.  7098 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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