title: Prostaglandin E2 induces CYP1B1 expression via ligand-independent activation of the ERalpha pathway in human breast cancer cells.
abstract: Breast cancer is a major cause of death worldwide. Human cytochrome P450 (CYP) 1B1 is a key enzyme in the metabolism of 17beta-estradiol, and CYP1B1-metabolized 4-hydroxyestradiol is a marker for breast cancer. Furthermore, overexpression of cyclooxygenase-2 (COX-2), which produces prostaglandin E(2) (PGE(2)), has been detected in invasive breast carcinomas. However, the interaction between PGE(2) and CYP1B1 expression in human breast cancer is unclear. Here, we investigated the effect of PGE(2) on CYP1B1 expression and its mechanism in breast cancer cells. PGE(2) 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 PGE(2). CYP1B1 expression was not affected by PGE(2) in estrogen receptor (ER) alpha-negative MDA-MB-231 breast cancer cells or in ERalpha/beta-negative MCF-10A normal breast cells, and protein expression of ERalpha and ERbeta was not affected by PGE(2) treatment in MCF-7 cells. However, PGE(2) rapidly induced phosphorylation of ERalpha at serine residues 118, 167, and 305, suggesting that PGE(2) activates ERalpha in a ligand-independent manner. PGE(2) also increased phosphorylation of extracellular signal-regulated kinase (ERK), Akt, and protein kinase A (PKA). Finally, a COX-2 inhibitor inhibited PGE(2)-induced CYP1B1 expression, and COX-2 overexpression increased CYP1B1 expression. Our results indicate that PGE(2)-induced CYP1B1 expression is mediated by ligand-independent activation of the ERalpha pathway as a result of the activation of ERK, Akt, and PKA in breast cancer cells.
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea.
authors.forename: Eun H
authors.initials: EH
authors.lastname: Han
authors.forename: Hyung G
authors.initials: HG
authors.lastname: Kim
authors.forename: Young P
authors.initials: YP
authors.lastname: Hwang
authors.forename: Gye Yong
authors.initials: GY
authors.lastname: Song
authors.forename: Hye G
authors.initials: HG
authors.lastname: Jeong
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D065633:Cytochrome P-450 CYP1B1; D015232:Dinoprostone / Q000235:genetics* / Q000378:metabolism; D004790:Enzyme Induction / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008024:Ligands; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008024:Ligands; D012333:RNA, Messenger; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone