Estrogen-mediated high reactive oxygen species (ROS) tolerance plays an important role in driving carcinogenesis. ROS overproduction acts as the significant effector to increase genomic instability and transduce redox-related signal pathway. Especially, estrogen-mediated mitochondrial ROS promote the mutations in mitochondrial DNA (mtDNA) and the damage to mitochondrial proteins. Moreover, estrogen-mediated ROS contribute to the alteration of energy metabolism and modulate several redox-sensitive proteins responsible for cell proliferation and anti-apoptosis. On the other hand, estrogen simultaneously performs the antioxidative beneficial functions, which protects cancer cells from the potential cytotoxic effects of estrogen-mediated ROS through activation of nuclear factor-erythroid-2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) antioxidant response. Consequently, estrogen potentiates the high ROS tolerance through increase of ROS production as well as acceleration of ROS elimination, which ultimately results in estrogen-mediated carcinogenesis and malignant transformation. However, this overdependence on antioxidant response system to resist ROS-mediated cytotoxicity also represents the "Achilles' Heel" of estrogen-mediated cancer cells. In other words, the destruction of the high ROS tolerance using antioxidant inhibitors may provide a novel and efficacious measure to selectively eliminate these cancer cells without harming normal cells. Of course, it will be necessary to define the exact situation of ROS homeostasis in the different cellular microenvironment and further decipher the mechanisms of redox regulation, which is consequently used as a new avenue to optimize the clinical therapy for estrogen-mediated cancer.
Keywords: Antioxidant response; Estrogen; ROS tolerance; Reactive oxygen species (ROS).