Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling

Cell Metab. 2018 Jul 3;28(1):69-86.e6. doi: 10.1016/j.cmet.2018.06.006.


Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic or oxidative stress generated by 2DG, H2O2, or hypoxia promotes the transition of ROSlo M-BCSCs to a ROShi E-state. This transition is reversed by N-acetylcysteine and mediated by activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROS-induced differentiation and cytotoxicity following suppression of NRF2 or downstream thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Co-inhibition of glycolysis and TXN and GSH pathways suppresses tumor growth, tumor-initiating potential, and metastasis by eliminating both M- and E-BCSCs. Exploiting metabolic vulnerabilities of distinct BCSC states provides a novel therapeutic approach targeting this critical tumor cell population.

Keywords: HIF1α; NRF2; antioxidant responses; cancer stem cell metabolism; cancer stem cell plasticity; glycolysis; hypoxia; oxidative phosphorylation.

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Acetylcysteine / metabolism*
  • Animals
  • Antioxidants / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic*
  • Female
  • Glucose / metabolism
  • Glutathione / metabolism
  • Glycolysis
  • Humans
  • Mice, Inbred NOD
  • NF-E2-Related Factor 2 / metabolism
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism*
  • Oxidation-Reduction
  • Oxidative Stress
  • Protein Kinases / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Stress, Physiological
  • Thioredoxins / metabolism
  • Xenograft Model Antitumor Assays


  • Antioxidants
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Reactive Oxygen Species
  • Thioredoxins
  • Protein Kinases
  • AMP-Activated Protein Kinase Kinases
  • Glutathione
  • Glucose
  • Acetylcysteine