title: Resveratrol suppresses 4-hydroxyestradiol-induced transformation of human breast epithelial cells by blocking IκB kinaseβ-NF-κB signalling.
abstract: Excess estrogen stimulates the proliferation of mammary epithelial cells and hence represents a major risk factor for breast cancer. Estrogen is subjected to cytochrome P450-catalysed oxidative metabolism to produce an oncogenic catechol estrogen, 4-hydroxyestradiol (4-OHE₂). 4-OHE₂ undergoes redox cycling during which reactive oxygen species (ROS) as well as the chemically reactive estrogen semiquinone and quinone intermediates are produced, thereby contributing to hormonal carcinogenesis. Resveratrol (3,4',5-trihydroxy stilbene), a phytoalexin present in grapes, has been reported to possess chemopreventive and chemotherapeutic activities. In the present study, we examined the inhibitory effects of resveratrol on 4-OHE₂-induced transformation of human breast epithelial MCF-10A cells. Resveratrol inhibited migration and anchorage-independent growth of MCF-10A cells treated with 4-OHE₂. Resveratrol treatment suppressed the 4-OHE₂-induced activation of IκB kinaseβ (IKKβ) and phosphorylation of IκBα, and consequently NF-κB DNA binding activity and cyclooxygenase-2 (COX-2) expression. Resveratrol suppressed ROS production and phosphorylation of Akt and ERK induced by 4-OHE₂ treatment. In conclusion, resveratrol blocks activation of IKKβ-NF-κB signalling and induction of COX-2 expression in 4-OHE₂-treated MCF-10A cells, thereby suppressing migration and transformation of these cells.
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Sin-Aye
authors.initials: SA
authors.lastname: Park
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Na
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002393:Estrogens, Catechol / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D002393:Estrogens, Catechol; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013267:Stilbenes; C014036:4-hydroxyestradiol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D000077185:Resveratrol