Abstract P1-02-09: Targeting breast cancer stem cell state equilibrium through modulation of redox signaling

Abstract

Abstract Breast cancer stem cells (BCSCs) maintain the plasticity to transition between quiescent mesenchymal- (M) and proliferative epithelial-like (E) states, but how this plasticity is regulated under metabolic/oxidative stress is poorly understood. Here, we show that M- and E-BCSCs exhibit markedly different sensitivities to the inhibitors of glycolysis and redox metabolism. Metabolic/Oxidative stress generated by 2DG/H2O2 or hypoxia promotes ROSlo M-BCSCs transition to their ROShi E-state. This transition is reversed by the antioxidant N-acetyl cysteine and facilitated by the activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust expression of NRF2/NFE2L2 and a wide variety of NRF2 downstream antioxidant responsive genes including the family of drug transporters and detoxification enzymes, NADPH production as well as the thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Suppression of NRF2 activity by a small-molecular inhibitor Trigonelline or shNRF2 mediated knockdown significantly decreased ALDH+ E- but not CD24-CD44+ M-BCSCs. This specific vulnerability of E-BCSCs to the inhibition of NRF2-mediated antioxidant defenses was also observed following inhibition of the downstream TXN and GSH antioxidant pathways, which promotes ROS-mediated differentiation and subsequent apoptosis of E-BCSCs. Co-inhibition of glycolysis and TXN/GSH pathways synergistically suppressed tumor growth and tumor initiating potential in two patient-derived xenograft models of triple negative breast cancer by eliminating both M- and E-BCSCs. Together, our studies reveal novel cellular and molecular mechanisms demonstrating how modulation of redox signaling regulates the equilibrium of two distinct BCSC states. These studies define the metabolic vulnerabilities of M- and E-BCSCs, and also provide a novel therapeutic approach to collectively target these distinct CSC states. As the CSC state equilibrium may be similarly regulated across a spectrum of tumors with diverse oncogenic drivers, this approach may have broad therapeutic applicability. Citation Format: Luo M, Shang L, Brooks M, Jiagge E, Zhu Y, Conley S, Fath MA, Harouaka R, Merajver SD, Spitz DR, Wicha MS. Targeting breast cancer stem cell state equilibrium through modulation of redox signaling [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-02-09.