Hydroxytyrosol inhibits cancer stem cells and the metastatic capacity of triple-negative breast cancer cell lines by the simultaneous targeting of epithelial-to-mesenchymal transition, Wnt/β-catenin and TGFβ signaling pathways

Purpose This study was aimed to determine the impact of hydroxytyrosol (HT), a minor compound found in olive oil, on breast cancer stem cells (BCSCs) and the migration capacity of triple-negative breast cancer (TNBC) cell lines through the alteration of epithelial-to-mesenchymal transition (EMT) and...

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Bibliographic Details
Published in:	European journal of nutrition 2019-12, Vol.58 (8), p.3207-3219
Main Authors:	Cruz-Lozano, Marina, González-González, Adrián, Marchal, Juan A., Muñoz-Muela, Esperanza, Molina, Maria P., Cara, Francisca E., Brown, Anthony M., García-Rivas, Gerardo, Hernández-Brenes, Carmen, Lorente, Jose A., Sanchez-Rovira, Pedro, Chang, Jenny C., Granados-Principal, Sergio
Format:	Article
Language:	eng
Subjects:	Aldehyde dehydrogenase Antioxidants - pharmacology beta Catenin - drug effects Blotting, Western Breast cancer CD44 antigen Cell adhesion & migration Cell migration Cell self-renewal Chemistry Chemistry and Materials Science Cyclin D1 D1 protein Dehydrogenases Embryos Epithelial-Mesenchymal Transition - drug effects Flow Cytometry Humans Mesenchyme Metastases Neoplastic Stem Cells - drug effects Nutrition Olive oil Original Contribution Phenylethyl Alcohol - analogs & derivatives Phenylethyl Alcohol - pharmacology Signal transduction Smad protein Smad2 protein Stem cells Transforming Growth Factor beta - drug effects Triple Negative Breast Neoplasms - drug therapy Tumor cell lines Tumor Cells, Cultured Vimentin Wnt protein Wnt Signaling Pathway - drug effects Wound healing β-Catenin
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Summary:	Purpose This study was aimed to determine the impact of hydroxytyrosol (HT), a minor compound found in olive oil, on breast cancer stem cells (BCSCs) and the migration capacity of triple-negative breast cancer (TNBC) cell lines through the alteration of epithelial-to-mesenchymal transition (EMT) and embryonic signaling pathways. Methods BCSCs self-renewal was determined by the mammosphere-forming efficiency in SUM159PT, BT549, MDA-MB-231 and Hs578T TNBC cell lines. Flow cytometric analysis of CD44 + /CD24 −/low and aldehyde dehydrogenase positive (ALDH + ) subpopulations, migration by the “wound healing assay”, invasion and Western blot of EMT markers and TGFβ signaling were investigated in SUM159PT, BT549 and MDA-MB-231 cell lines. Wnt/β-catenin signaling was assessed by Western blot in BT549 cells expressing WNT1 and MDA-MB-231 cells. Changes in TGFβ activity was determined by SMAD Binding Element (SBE) reporter assay. Results HT reduced BCSCs self-renewal, ALDH + (aldehyde dehydrogenase) and CD44 + /CD24 −/low subpopulations, tumor cell migration and invasion. Consistently, HT suppressed Wnt/β-catenin signaling by decreasing p-LRP6, LRP6, β-catenin and cyclin D1 protein expression and the EMT markers SLUG, ZEB1, SNAIL and VIMENTIN. Finally, HT inhibited p-SMAD2/3 and SMAD2/3 in SUM159PT, BT549 and MDA-MB-231 cells, what was correlated with a less TGFβ activity. Conclusion In conclusion, we report for the first time the inhibitory role of HT on BCSCs and tumor cell migration by targeting EMT, Wnt/β-catenin and TGFβ signaling pathways. Our findings highlight the importance of the chemopreventive compound HT as a novel candidate to be investigated as an alternative targeted therapy for TNBC.
ISSN:	1436-6207 1436-6215