title: 4-hydroxyestradiol induces anchorage-independent growth of human mammary epithelial cells via activation of IkappaB kinase: potential role of reactive oxygen species.
abstract: Estrogen is converted by cytochrome P450 1B1 to 4-hydroxyestradiol (4-OHE(2)), a putative carcinogenic metabolite of estrogen. This catechol estrogen metabolite is oxidized further to produce a reactive quinone via semiquinone. Redox cycling between 4-OHE(2) and its quinoid generates reactive oxygen species (ROS). ROS not only causes oxidative DNA damage but also promotes neoplastic transformation of initiated cells. In the present study, 4-OHE(2) induced anchorage-independent colony formation in human mammary epithelial cells (MCF-10A). MCF-10A cells treated with 4-OHE(2) exhibited increased accumulation of intracellular ROS. The antioxidant N-acetyl-l-cysteine inhibited the neoplastic transformation induced by 4-OHE(2). ROS overproduced by 4-OHE(2) increased the nuclear translocation of nuclear factor-kappaB (NF-kappaB) and its DNA binding through induction of IkappaB kinase alpha (IKKalpha) and IKKbeta activities. The inhibition of the IKK activities with Bay 11-7082 significantly reduced the anchorage-independent growth induced by 4-OHE(2). The 4-OHE(2)-induced activation of extracellular signal-regulated kinase and Akt resulted in enhanced IKK activities and phosphorylation of IkappaBalpha, thereby inducing NF-kappaB activation and anchorage-independent growth of MCF-10A cells. In conclusion, ROS, concomitantly overproduced during redox cycling of 4-OHE(2), activates IKK signaling, which may contribute to neoplastic transformation of MCF-10A cells.
authors.affiliation: National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, 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: Eun-Hee
authors.initials: EH
authors.lastname: Kim
authors.forename: Young-Nam
authors.initials: YN
authors.lastname: Cha
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D001940:Breast / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002393:Estrogens, Catechol; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002393:Estrogens, Catechol; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D004958:Estradiol; D004247:DNA; C014036:4-hydroxyestradiol; D051058:Oncogene Protein v-akt; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases