Format

Send to

Choose Destination
Eur J Nutr. 2018 Nov 21. doi: 10.1007/s00394-018-1864-1. [Epub ahead of print]

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.

Author information

1
UGC de Oncología Médica, Complejo Hospitalario de Jaén, Avenida del Ejército Español 10, Jaén, Spain.
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.
3
Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Universidad de Granada, Granada, Spain.
4
Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.
5
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, USA.
6
Centro de Investigación Biomédica, Hospital Zambrano Hellion, Tecnológico de Monterrey, Monterrey, NL, Mexico.
7
Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX, USA.
8
UGC de Oncología Médica, Complejo Hospitalario de Jaén, Avenida del Ejército Español 10, Jaén, Spain. sergio.granados.exts@juntadeandalucia.es.
9
GENYO. Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada -Avenida de la Ilustración, 114-18016, Granada, Spain. sergio.granados.exts@juntadeandalucia.es.

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.

KEYWORDS:

Cancer stem cells; Epithelial-to-mesenchymal transition; Hydroxytyrosol; Olive oil; Triple-negative breast cancer

PMID:
30460610
DOI:
10.1007/s00394-018-1864-1

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center