Chronic Oxidative Stress Promotes Molecular Changes Associated with Epithelial Mesenchymal Transition, NRF2, and Breast Cancer Stem Cell Phenotype
Open Access
- 11 December 2019
- journal article
- research article
- Published by MDPI AG in Antioxidants
- Vol. 8 (12), 633
- https://doi.org/10.3390/antiox8120633
Abstract
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.Funding Information
- OeNB (No´14001)
This publication has 45 references indexed in Scilit:
- Genetic and epigenetic analysis of putative breast cancer stem cell modelsBMC Cancer, 2013
- Novel Immunofluorescence Protocol for Multimarker Assessment of Putative Disseminating Breast Cancer Stem CellsApplied Immunohistochemistry & Molecular Morphology, 2011
- Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypesProceedings of the National Academy of Sciences of the United States of America, 2010
- Human colon cancer epithelial cells harbour active HEDGEHOG‐GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansionEMBO Molecular Medicine, 2009
- The basics of epithelial-mesenchymal transitionJCI Insight, 2009
- Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast CancerThe New England Journal of Medicine, 2009
- Reactive Aldehyde Modification of Thioredoxin-1 Activates Early Steps of Inflammation and Cell AdhesionThe American Journal of Pathology, 2007
- ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical OutcomeCell Stem Cell, 2007
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976
- THE DISTRIBUTION OF SECONDARY GROWTHS IN CANCER OF THE BREAST.The Lancet, 1889