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

European Journal of Nutrition volume 58, pages3207–3219(2019)Cite this article

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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References

  1. 1.

    Foulkes WD, Smith IE, Reis-Filho JS (2010) Triple-negative breast cancer. N Engl J Med 363:1938–1948. https://doi.org/10.1056/NEJMra1001389

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    González-González A, Muñoz-Muela E, Marchal JA et al (2018) Activating transcription factor 4 modulates TGFβ-induced aggressiveness in triple negative breast cancer via SMAD2/3/4 and mTORC2 signaling. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-17-3125

    Article  PubMed  Google Scholar 

  3. 3.

    Lehmann BD, Bauer JA, Chen X et al (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750–2767. https://doi.org/10.1172/JCI45014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Idowu MO, Kmieciak M, Dumur C et al (2012) CD44(+)/CD24(-/low) cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome. Hum Pathol 43:364–373. https://doi.org/10.1016/j.humpath.2011.05.005

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Bianchini G, Balko JM, Mayer IA et al (2016) Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol 13:674–690. https://doi.org/10.1038/nrclinonc.2016.66

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Al-Hajj M, Wicha MS, Benito-Hernandez A et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988. https://doi.org/10.1073/pnas.0530291100

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Ginestier C, Hur MH, Charafe-Jauffret E et al (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555–567. https://doi.org/10.1016/j.stem.2007.08.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Charafe-Jauffret E, Ginestier C, Iovino F et al (2009) Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69:1302–1313. https://doi.org/10.1158/0008-5472.CAN-08-2741

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Brooks MD, Burness ML, Wicha MS (2015) Therapeutic implications of cellular heterogeneity and plasticity in breast cancer. Cell Stem Cell 17:260–271. https://doi.org/10.1016/j.stem.2015.08.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Mani SA, Guo W, Liao M et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715. https://doi.org/10.1016/j.cell.2008.03.027

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Takebe N, Warren RQ, Ivy SP (2011) Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition. Breast Cancer Res 13:211. https://doi.org/10.1186/bcr2876

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Kalluri R, Weinberg RA (2009) The basics of epithelial–mesenchymal transition. J Clin Invest 119:1420–1428. https://doi.org/10.1172/JCI39104

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Fischer KR, Durrans A, Lee S et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472–476. https://doi.org/10.1038/nature15748

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Granados-Principal S, Quiles JL, Ramirez-Tortosa CL et al (2010) Hydroxytyrosol: from laboratory investigations to future clinical trials. Nutr Rev 68:191–206. https://doi.org/10.1111/j.1753-4887.2010.00278.x

    Article  PubMed  Google Scholar 

  15. 15.

    Granados-Principal S, Quiles JL, Ramirez-Tortosa CL et al (2012) Squalene ameliorates atherosclerotic lesions through the reduction of CD36 scavenger receptor expression in macrophages. Mol Nutr Food Res 56:733–740. https://doi.org/10.1002/mnfr.201100703

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Granados-Principal S, Quiles JL, Ramirez-Tortosa CL et al (2010) New advances in molecular mechanisms and the prevention of adriamycin toxicity by antioxidant nutrients. Food Chem Toxicol 48:1425–1438. https://doi.org/10.1016/j.fct.2010.04.007

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Granados-Principal S, El-Azem N, Pamplona R et al (2014) Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer. Biochem Pharmacol 90:25–33. https://doi.org/10.1016/j.bcp.2014.04.001

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Granados-Principal S, Quiles JL, Ramirez-Tortosa C et al (2011) Hydroxytyrosol inhibits growth and cell proliferation and promotes high expression of sfrp4 in rat mammary tumours. Mol Nutr Food Res 55(Suppl 1):S117–S126. https://doi.org/10.1002/mnfr.201000220

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Dass RA, Sarshad AA, Carson BB et al (2016) Wnt5a signals through DVL1 to repress ribosomal DNA transcription by RNA polymerase I. PLoS Genet 12:e1006217. https://doi.org/10.1371/journal.pgen.1006217

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Choi DS, Blanco E, Kim Y-S et al (2014) Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. Stem Cells 32:2309–2323. https://doi.org/10.1002/stem.1746

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Dave B, Granados-Principal S, Zhu R et al (2014) Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling. Proc Natl Acad Sci USA 111:8838–8843. https://doi.org/10.1073/pnas.1320769111

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Granados-Principal S, Liu Y, Guevara ML et al (2015) Inhibition of iNOS as a novel effective targeted therapy against triple-negative breast cancer. Breast Cancer Res 17:25. https://doi.org/10.1186/s13058-015-0527-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Chiang K, Zielinska AE, Shaaban AM et al (2017) PRMT5 is a critical regulator of breast cancer stem cell function via histone methylation and FOXP1 expression. Cell Rep 21:3498–3513. https://doi.org/10.1016/j.celrep.2017.11.096

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Liu S, Cong Y, Wang D et al (2014) Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep 2:78–91. https://doi.org/10.1016/j.stemcr.2013.11.009

    CAS  Article  Google Scholar 

  25. 25.

    Liu C-C, Prior J, Piwnica-Worms D, Bu G (2010) LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy. Proc Natl Acad Sci USA 107:5136–5141. https://doi.org/10.1073/pnas.0911220107

    Article  PubMed  Google Scholar 

  26. 26.

    King TD, Suto MJ, Li Y (2012) The Wnt/β-catenin signaling pathway: a potential therapeutic target in the treatment of triple negative breast cancer. J Cell Biochem 113:13–18. https://doi.org/10.1002/jcb.23350

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Guo W, Keckesova Z, Donaher JL et al (2012) Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 148:1015–1028. https://doi.org/10.1016/j.cell.2012.02.008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Jitariu A, Cîmpean AM, Ribatti D, Raica M (2017) Triple negative breast cancer: the kiss of death. Oncotarget 8:46652–46662. https://doi.org/10.18632/oncotarget.16938

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Bhola NE, Balko JM, Dugger TC et al (2013) TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest 123:1348–1358. https://doi.org/10.1172/JCI65416

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Jhan J-R, Andrechek ER (2017) Effective personalized therapy for breast cancer based on predictions of cell signaling pathway activation from gene expression analysis. Oncogene 36:3553–3561. https://doi.org/10.1038/onc.2016.503

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Li X, Lewis MT, Huang J et al (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100:672–679. https://doi.org/10.1093/jnci/djn123

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Diehn M, Cho RW, Lobo NA et al (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458:780–783. https://doi.org/10.1038/nature07733

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Creighton CJ, Li X, Landis M et al (2009) Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA 106:13820–13825. https://doi.org/10.1073/pnas.0905718106

    Article  PubMed  Google Scholar 

  34. 34.

    Liedtke C, Mazouni C, Hess KR et al (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26:1275–1281. https://doi.org/10.1200/JCO.2007.14.4147

    Article  Google Scholar 

  35. 35.

    Li Y, Wicha MS, Schwartz SJ, Sun D (2011) Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J Nutr Biochem 22:799–806. https://doi.org/10.1016/j.jnutbio.2010.11.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Kakarala M, Brenner DE, Korkaya H et al (2010) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 122:777–785. https://doi.org/10.1007/s10549-009-0612-x

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Li Y, Zhang T, Korkaya H et al (2010) Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 16:2580–2590. https://doi.org/10.1158/1078-0432.CCR-09-2937

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Avtanski DB, Nagalingam A, Bonner MY et al (2014) Honokiol inhibits epithelial-mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis. Mol Oncol 8:565–580. https://doi.org/10.1016/j.molonc.2014.01.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Charpentier MS, Whipple RA, Vitolo MI et al (2014) Curcumin targets breast cancer stem-like cells with microtentacles that persist in mammospheres and promote reattachment. Cancer Res 74:1250–1260. https://doi.org/10.1158/0008-5472.CAN-13-1778

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Fu Y, Chang H, Peng X et al (2014) Resveratrol inhibits breast cancer stem-like cells and induces autophagy via suppressing Wnt/β-catenin signaling pathway. PLoS One 9:e102535. https://doi.org/10.1371/journal.pone.0102535

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Wang N, Wang Z, Wang Y et al (2015) Dietary compound isoliquiritigenin prevents mammary carcinogenesis by inhibiting breast cancer stem cells through WIF1 demethylation. Oncotarget 6:9854–9876. https://doi.org/10.18632/oncotarget.3396

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Fu J, Ke X, Tan S et al (2016) The natural compound codonolactone attenuates TGF-β1-mediated epithelial-to-mesenchymal transition and motility of breast cancer cells. Oncol Rep 35:117–126. https://doi.org/10.3892/or.2015.4394

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Sun M, Zhang N, Wang X et al (2016) Hedgehog pathway is involved in nitidine chloride induced inhibition of epithelial–mesenchymal transition and cancer stem cells-like properties in breast cancer cells. Cell Biosci 6:44. https://doi.org/10.1186/s13578-016-0104-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Wang N, Wang Q, Tang H et al (2017) Direct inhibition of ACTN4 by ellagic acid limits breast cancer metastasis via regulation of β-catenin stabilization in cancer stem cells. J Exp Clin Cancer Res 36:172. https://doi.org/10.1186/s13046-017-0635-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Li X, Meng Y, Xie C et al (2018) Diallyl Trisulfide inhibits breast cancer stem cells via suppression of Wnt/β-catenin pathway. J Cell Biochem 119:4134–4141. https://doi.org/10.1002/jcb.26613

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Christian MS, Sharper VA, Hoberman AM et al (2004) The toxicity profile of hydrolyzed aqueous olive pulp extract. Drug Chem Toxicol 27:309–330. https://doi.org/10.1081/DCT-200039714

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    González-Santiago M, Fonollá J, Lopez-Huertas E (2010) Human absorption of a supplement containing purified hydroxytyrosol, a natural antioxidant from olive oil, and evidence for its transient association with low-density lipoproteins. Pharmacol Res 61:364–370. https://doi.org/10.1016/j.phrs.2009.12.016

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Khymenets O, Fitó M, Touriño S et al (2010) Antioxidant activities of hydroxytyrosol main metabolites do not contribute to beneficial health effects after olive oil ingestion. Drug Metab Dispos 38:1417–1421. https://doi.org/10.1124/dmd.110.032821

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Corominas-Faja B, Cuyàs E, Lozano-Sánchez J et al (2018) Extra-virgin olive oil contains a metabolo-epigenetic inhibitor of cancer stem cells. Carcinogenesis 39:601–613. https://doi.org/10.1093/carcin/bgy023

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Wang Q-L, Tao Y-Y, Yuan J-L et al (2010) Salvianolic acid B prevents epithelial-to-mesenchymal transition through the TGF-beta1 signal transduction pathway in vivo and in vitro. BMC Cell Biol 11:31. https://doi.org/10.1186/1471-2121-11-31

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Davies AH, Reipas K, Hu K et al (2015) Inhibition of RSK with the novel small-molecule inhibitor LJI308 overcomes chemoresistance by eliminating cancer stem cells. Oncotarget 6:20570–20577. https://doi.org/10.18632/oncotarget.4135

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Li Y, Jiang F, Chen L et al (2015) Blockage of TGFβ-SMAD2 by demethylation-activated miR-148a is involved in caffeic acid-induced inhibition of cancer stem cell-like properties in vitro and in vivo. FEBS Open Bio 5:466–475. https://doi.org/10.1016/j.fob.2015.05.009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Dandawate PR, Subramaniam D, Jensen RA, Anant S (2016) Targeting cancer stem cells and signaling pathways by phytochemicals: novel approach for breast cancer therapy. Semin Cancer Biol 40–41:192–208. https://doi.org/10.1016/j.semcancer.2016.09.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Farahmand L, Darvishi B, Majidzadeh -AK, Madjid Ansari A (2017) Naturally occurring compounds acting as potent anti-metastatic agents and their suppressing effects on Hedgehog and WNT/β-catenin signalling pathways. Cell Prolif. https://doi.org/10.1111/cpr.12299

    Article  PubMed  Google Scholar 

  55. 55.

    Lin D, Kuang G, Wan J et al (2017) Luteolin suppresses the metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via downregulation of β-catenin expression. Oncol Rep 37:895–902. https://doi.org/10.3892/or.2016.5311

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Bhuvanalakshmi G, Rangappa KS et al (2017) Breast cancer stem-like cells are inhibited by diosgenin, a steroidal saponin, by the attenuation of the Wnt β-Catenin signaling via the Wnt antagonist secreted frizzled related protein-4. Front Pharmacol 8:124. https://doi.org/10.3389/fphar.2017.00124

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Li Y, Lu W, King TD et al (2010) Dkk1 stabilizes Wnt co-receptor LRP6: implication for Wnt ligand-induced LRP6 down-regulation. PLoS One 5:e11014. https://doi.org/10.1371/journal.pone.0011014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Guo X, Wang X-F (2009) Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res 19:71–88. https://doi.org/10.1038/cr.2008.302

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Zhou B, Liu Y, Kahn M et al (2012) Interactions between β-catenin and transforming growth factor-β signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem 287:7026–7038. https://doi.org/10.1074/jbc.M111.276311

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Murillo-Garzón V, Gorroño-Etxebarria I, Åkerfelt M et al (2018) Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer. Nat Commun 9:1747. https://doi.org/10.1038/s41467-018-04042-w

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Sundqvist A, Morikawa M, Ren J et al (2018) JUNB governs a feed-forward network of TGFβ signaling that aggravates breast cancer invasion. Nucleic Acids Res 46:1180–1195. https://doi.org/10.1093/nar/gkx1190

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    El-Azem N, Pulido-Moran M, Ramirez-Tortosa CL et al (2018) Modulation by hydroxytyrosol of oxidative stress and antitumor activities of paclitaxel in breast cancer. Eur J Nutr 0:1–9. https://doi.org/10.1007/s00394-018-1638-9

    CAS  Article  Google Scholar 

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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”.

Author information

Author notes

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

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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  2. Adrián González-González
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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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Keywords

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