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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

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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.

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Acknowledgements

Funding was provided by Instituto de Salud Carlos III (CP14/00197, PI15/00336, PIE16/00045), European Regional Development Fund (European Union), and the Chair “Doctors Galera-Requena in Cancer Stem Cell Research”.

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Author notes

  1. Marina Cruz-Lozano and Adrián González-González contributed equally.

Authors and Affiliations

  1. UGC de Oncología Médica, Complejo Hospitalario de Jaén, Avenida del Ejército Español 10, Jaén, Spain

    Marina Cruz-Lozano, Adrián González-González, Esperanza Muñoz-Muela, Maria P. Molina, Francisca E. Cara, Pedro Sanchez-Rovira & Sergio Granados-Principal

  2. GENYO. Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada -Avenida de la Ilustración, 114-18016, Granada, Spain

    Marina Cruz-Lozano, Adrián González-González, Esperanza Muñoz-Muela, Maria P. Molina, Francisca E. Cara, Jose A. Lorente, Pedro Sanchez-Rovira & Sergio Granados-Principal

  3. Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Universidad de Granada, Granada, Spain

    Juan A. Marchal

  4. Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain

    Juan A. Marchal

  5. Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, USA

    Anthony M. Brown

  6. Centro de Investigación Biomédica, Hospital Zambrano Hellion, Tecnológico de Monterrey, Monterrey, NL, Mexico

    Gerardo García-Rivas & Carmen Hernández-Brenes

  7. Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX, USA

    Jenny C. Chang

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  1. Marina Cruz-Lozano
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Cruz-Lozano, M., González-González, A., Marchal, J.A. et al. 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. Eur J Nutr 58, 3207–3219 (2019). https://doi.org/10.1007/s00394-018-1864-1

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