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Estrogen potentiates reactive oxygen species (ROS) tolerance to initiate carcinogenesis and promote cancer malignant transformation

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Tumor Biology

Abstract

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.

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Acknowledgments

This project was supported by the National Natural Science Foundation of China (Nos. 81202144; 81202015; 81400055). Science and Technology Department of Jiangsu province natural fund youth project (No: BK20140242)

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    1. Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, Jiangsu, 221002, People’s Republic of China

      Hui Tian, Zhen Gao, Gang Wang & Huizhong Li

    2. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu, 221002, China

      JunNian Zheng

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    Hui Tian and Zhen Gao contributed equally to this work.

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    Tian, H., Gao, Z., Wang, G. et al. Estrogen potentiates reactive oxygen species (ROS) tolerance to initiate carcinogenesis and promote cancer malignant transformation. Tumor Biol. 37, 141–150 (2016). https://doi.org/10.1007/s13277-015-4370-6

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