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

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

^* To whom correspondence should be addressed. E-mail: surh{at}plaza.snu.ac.kr.

	Abstract

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 IKK 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]

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

This article has been cited by other articles:

				M.-H. Lee, B. Y. Choi, J. K. Kundu, Y. K. Shin, H.-K. Na, and Y.-J. Surh Resveratrol Suppresses Growth of Human Ovarian Cancer Cells in Culture and in a Murine Xenograft Model: Eukaryotic Elongation Factor 1A2 as a Potential Target Cancer Res., September 15, 2009; 69(18): 7449 - 7458. [Abstract] [Full Text] [PDF]