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10 Introduction 11 Generation of genotoxic metabolites of estrogen as a potential mechanism of breast carcinogenicity 15 Estrogen receptor mediated carcinogenic actions 18 Estrogen, mitochondria, and ROS generation 19 Estrogen and mitochondria 20 Mitochondria and generation of estrogen induced ROS 21 Estrogen-induced ROS-mediated oxidative DNA damages 23 Estrogen-induced ROS mediated redox signalings 25 Regulation of phosphatases by estrogen-induced ROS 26 Activation of kinases by estrogen-induced ROS A-Raf ERK AKT 30 31 32 33 Activation of redox sensitive transcription factors by estrogeninduced oxidants signaling ER AP-1 and CREB NF-kB NRF1 35 35 37 41 42 Role of estrogen-induced redox signaling in the development of breast cancer 46 Estrogen-induced ROS as potential mediator of cell transformation and generators of human breast cancer stem cells 46 Estrogen-induced ROS as mediators of cell cycle progression 48 Estrogen-induced ROS as mediators of breast cancer progression 54 Estrogen induced ROS, NRF1 and therapeutic resistance 57 Summary 59 Figures and legends 91

4-Hydroxy Estradiol-Induced Oxidant-Mediated Signaling Is Involved In The Development Of Breast Cancer