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Antioxid Redox Signal. 2019 Nov 1. doi: 10.1089/ars.2019.7730. [Epub ahead of print]

Nrf2-induced reductive stress favours self-renewal of breast cancer stem-like cells via the FoxO3a-Bmi-1 axis.

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Seoul National University, Pharmacy, 142-509, Seoul National Univer., Seoul, Korea (the Republic of);
Seoul National University, 26725, Pharmacy, Gwanak-gu, Seoul, Korea (the Republic of);
Seoul National University, Seoul, Korea (the Republic of);
Seoul National University, Seoul, Korea (the Republic of);
Keimyung University, 26722, Department of Pharmacy,, Daegu, Korea (the Republic of);
Seoul National University, College of Pharmacy, Shillim-dong, Kwanak-gu, Seoul, Korea (the Republic of), 151-742;



A subpopulation of cancer cells, termed cancer stem cells (CSCs), has stemness properties, such as self-renewal and differentiation, which drive cancer recurrence and tumor resistance. CSCs possess enhanced protection capabilities to maintain reduced intracellular levels of reactive oxygen species (ROS) compared to non-stem-like cancer cells. This study investigated whether reductive stress could regulate self-renewal activity in breast CSCs.


We found that manifestation of stemness in breast cancer stem-like cells was associated with an elevated production of reduced glutathione (GSH) maintained by upregulation of glutamate cysteine ligase catalytic subunit (GCLC) and consequently, lowered ROS levels. This was accompanied by upregulation of P-AMPK, FoxO3a and Bmi-1. Notably, expression of Nrf2 protein was substantially increased in cells undergoing sphere formation. We noticed that expression of FoxO3a was inhibited following introduction of Nrf2 siRNA into MCF-7 mammosphere cells. Silencing of Nrf2 expression suppressed the xenograft growth of subcutaneously or orthotopically injected human breast cancer cells. Innovations: Association between Nrf2 and self-renewal signaling in CSCs has been reported, but the underling molecular mechanism remains largely unresolved. This study investigates Nrf2-mediated signaling pathway in maintenance of reductive stress in breast CSCs.


Nrf2 overactivation in breast CSCs, which, in turn, upregulate GCLC expression and consequently enhances GSH biosynthesis with concurrent reduction in intracellular ROS accumulation, provoking the reductive stress. The consequent upregulation of nuclear FoxO3a and its binding to the Bmi-1 promoter, may account for the self-renewal activity of breast cancer stem-like cells and their growth in a xenograft mouse model.


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