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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Movement
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Cell Proliferation
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Cell Transformation, Neoplastic / drug effects*
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Epithelial Cells / cytology
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Epithelial Cells / drug effects*
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Epithelial Cells / metabolism
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Estrogens, Catechol / pharmacology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression
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Humans
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I-kappa B Kinase / antagonists & inhibitors*
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism
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Mammary Glands, Human / cytology
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Mammary Glands, Human / drug effects
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Mammary Glands, Human / metabolism
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
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Resveratrol
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Signal Transduction
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Stilbenes / pharmacology*
Substances
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Estrogens, Catechol
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NF-kappa B
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Reactive Oxygen Species
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Stilbenes
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4-hydroxyestradiol
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Cyclooxygenase 2
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PTGS2 protein, human
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Proto-Oncogene Proteins c-akt
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I-kappa B Kinase
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Extracellular Signal-Regulated MAP Kinases
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Resveratrol