title: A positive feedback pathway of estrogen biosynthesis in breast cancer cells is contained by resveratrol.
abstract: Cytochrome P450 (CYP) 19 enzyme or aromatase catalyses the rate-determining step of estrogen synthesis. The transcriptional control of CYP19 gene is highly specific in different cell types, for instance, Promoter I.3/II is commonly used for regulation in breast cancer cells. Recently, a positive feedback pathway for estrogen synthesis has been identified in ER alpha expressing SK-BR-3 cells. CYP19 mRNA abundance and activity are increased in this pathway and the promoter usage is switched from Promoter I.3/II to I.1 through a non-genomic process. In the present study, effect of the phytocompound resveratrol on this Promoter I.1-controlled expression of aromatase was investigated. Results indicated that resveratrol reduced the estradiol-induced mRNA abundance in SK-BR-3 cells expressing ER alpha. Luciferase reporter gene assays revealed that resveratrol could also repress the transcriptional control dictated by Promoter I.1. Since the ERE-driven luciferase activity was not repressed by resveratrol, the nuclear events of estrogen were unlikely to be suppressed by resveratrol. Instead the phytochemical reduced the amount of ERK activated by estradiol, which could be the pathway responsible for Promoter I.1 transactivation and the induced CYP19 expression. The present study illustrated that resveratrol impeded the non-genomic induction of estrogen on CYP19.
authors.affiliation: Department of Biochemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Lan
authors.initials: L
authors.lastname: Ye
authors.forename: Lai K
authors.initials: LK
authors.lastname: Leung
mesh_terms: D001141:Aromatase / Q000096:biosynthesis / Q000235:genetics; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000096:biosynthesis*; D025461:Feedback, Physiological / Q000187:drug effects*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D004967:Estrogens; D012333:RNA, Messenger; D013267:Stilbenes; D001141:Aromatase; D000077185:Resveratrol