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4-Hydroxyestradiol Induces Anchorage-Independent Growth of Human Mammary Epithelial Cells via Activation of IB Kinase: Potential Role of Reactive Oxygen Species

¹ National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy and ² Cancer Research Institute, Seoul National University, Seoul, South Korea and ³ College of Medicine, Inha University, Incheon, South Korea

Requests for reprints: Young-Joon Surh or Hye-Kyung Na, College of Pharmacy, Seoul National University, Shillim-dong, Kwanak-gu, Seoul 151-742, South Korea. Phone: 82-2-880-7845; Fax: 82-2-874-9775; E-mail: surh{at}plaza.snu.ac.kr or nhk1228{at}snu.ac.kr.

Key Words: 4-hydroxyestradiol • catechol estrogen • IB kinase

Estrogen is converted by cytochrome P450 1B1 to 4-hydroxyestradiol (4-OHE₂), a putative carcinogenic metabolite of estrogen. This catechol estrogen metabolite is oxidized further to produce a reactive quinone via semiquinone. Redox cycling between 4-OHE₂ 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-OHE₂ induced anchorage-independent colony formation in human mammary epithelial cells (MCF-10A). MCF-10A cells treated with 4-OHE₂ exhibited increased accumulation of intracellular ROS. The antioxidant N-acetyl-L-cysteine inhibited the neoplastic transformation induced by 4-OHE₂. ROS overproduced by 4-OHE₂ increased the nuclear translocation of nuclear factor-B (NF-B) and its DNA binding through induction of IB kinase (IKK) and IKKβ activities. The inhibition of the IKK activities with Bay 11-7082 significantly reduced the anchorage-independent growth induced by 4-OHE₂. The 4-OHE₂–induced activation of extracellular signal-regulated kinase and Akt resulted in enhanced IKK activities and phosphorylation of IB, thereby inducing NF-B activation and anchorage-independent growth of MCF-10A cells. In conclusion, ROS, concomitantly overproduced during redox cycling of 4-OHE₂, activates IKK signaling, which may contribute to neoplastic transformation of MCF-10A cells. [Cancer Res 2009;69(6):2416–24]

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