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Antioxidants (Basel). 2019 Dec 11;8(12). pii: E633. doi: 10.3390/antiox8120633.

Chronic Oxidative Stress Promotes Molecular Changes Associated with Epithelial Mesenchymal Transition, NRF2, and Breast Cancer Stem Cell Phenotype.

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Division of Molecular Medicine, Ruđer Bošković Institute, HR-10000 Zagreb, Croatia.
Department of Internal Medicine, Division of Oncology, Medical University, Graz 8036, Austria.
Outhospital Emergency Medicine Department of Krapina Zagorje County, HR-49000 Krapina, Croatia.
Institute of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
Sestre milosrdnice University Hospital Centre, University Hospital for Tumors, HR-10000 Zagreb, Croatia.


Oxidative stress plays a role in carcinogenesis, but it also contributes to the modulation of tumor cells and microenvironment caused by chemotherapeutics. One of the consequences of oxidative stress is lipid peroxidation, which can, through reactive aldehydes such as 4-hydroxy-2-nonenal (HNE), affect cell signaling pathways. On the other hand, cancer stem cells (CSC) are now recognized as a major factor of malignancy by causing metastasis, relapse, and therapy resistance. Here, we evaluated whether oxidative stress and HNE modulation of the microenvironment can influence CSC growth, modifications of the epithelial to mesenchymal transition (EMT) markers, the antioxidant system, and the frequency of breast cancer stem cells (BCSC). Our results showed that oxidative changes in the microenvironment of BCSC and particularly chronic oxidative stress caused changes in the proliferation and growth of breast cancer cells. In addition, changes associated with EMT, increase in glutathione (GSH) and Nuclear factor erythroid 2-related factor 2 (NRF2) were observed in breast cancer cells grown on HNE pretreated collagen and under chronic oxidative stress. Our results suggest that chronic oxidative stress can be a bidirectional modulator of BCSC fate. Low levels of HNE can increase differentiation markers in BCSC, while higher levels increased GSH and NRF2 as well as certain EMT markers, thereby increasing therapy resistance.


4-hydroxy-2-nonenal; NRF2; breast cancer stem cells; extracellular matrix

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