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- Title
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.
- 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
- Abstract
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.
- Subjects
ALDEHYDE dehydrogenase; BIOMARKERS; BREAST tumors; CELL lines; CELL physiology; CELL motility; CELLULAR signal transduction; CYTOSKELETAL proteins; EPITHELIAL cells; ETHANOL; FLOW cytometry; METASTASIS; STEM cells; TRANSFORMING growth factors-beta; WESTERN immunoblotting
- Publication
European Journal of Nutrition, 2019, Vol 58, Issue 8, p3207
- ISSN
1436-6207
- Publication type
Article
- DOI
10.1007/s00394-018-1864-1