Pterostilbene, a bioactive component of blueberries, suppresses the generation of breast cancer stem cells within tumor microenvironment and metastasis via modulating NF-κB/microRNA 448 circuit

Authors

  • Ka-Kit Mak,

    1. Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
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    • These authors contributed equally to this work.

  • Alexander T. H. Wu,

    1. Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
    2. Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan
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    • These authors contributed equally to this work.

  • Wei-Hwa Lee,

    1. Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
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  • Tung-Cheng Chang,

    1. Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
    2. Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
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  • Jeng-Fong Chiou,

    1. Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan
    2. Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taiwan
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  • Liang-Shun Wang,

    1. Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
    2. Division of Thoracic Surgery, Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
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  • Chih-Hsiung Wu,

    1. Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
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  • Chi-Ying F. Huang,

    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
    2. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
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  • Yi-Shing Shieh,

    1. Department of Oral Diagnosis, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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  • Tsu-Yi Chao,

    1. Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
    2. Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
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  • Chi-Tang Ho,

    1. Department of Food Science, Rutgers University, New Brunswick, NJ, USA
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  • Gow-Chin Yen,

    Corresponding author
    1. Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan
    2. Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
    • Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
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  • Chi-Tai Yeh

    Corresponding author
    1. Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
    2. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
    • Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
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Correspondence: Dr. Chi-Tai Yeh, Graduate Institute of Clinical Medicine, Taipei Medical University, No. 250, Wu-Hsing street, Taipei, 11031 Taiwan

E-mail: ctyeh@tmu.edu.tw

Fax: +866-2-2245-0900

Additional corresponding author: Professor Gow-Chin Yen,

E-mail: gcyen@nchu.edu.tw

Abstract

Scope

Tumor-associated macrophages (TAMs) have been shown to promote metastasis and malignancy. Pterostilbene, a natural stilbene isolated from blueberries, has been suggested for anti-cancer effects. Here, we explored the potential cancer stem cells (CSCs)/TAM modulating effects of pterostilbene in breast cancer.

Methods and results

Using flowcytometric and Boyden chamber assay, we showed MCF7 and MDA-MB-231 cells cocultured with M2 TAMs exhibited increased percentage of CD44+/CD24 CSC population and migratory/invasive abilities. RT-PCR results showed that CD44+/CD24 cells expressed an increased level of HIF-1α, β-catenin, Twist1, and NF-κB and enhanced tumor sphere forming ability. Additionally, pterostilbene treatment dose dependently overcame M2 TAM-induced enrichment of CSCs and metastatic potential of breast cancer cells. Mechanistically, pterostilbene suppressed NFκB, Twist1, vimentin, and increased E-cadherin expression. Using siRNA technique, we demonstrated that pterostilbene-mediated NFκB downregulation was correlated to an increased amount of microRNA 448. Finally, pterostilbene-mediated suppression in tumorigenesis and metastasis was validated by noninvasive bioluminescence in mice bearing M2 TAM cocultured MDA-MB-231 tumor.

Conclusion

Pterostilbene effectively suppresses the generation of CSCs and metastatic potential under the influence of M2 TAMs via modulating EMT associated signaling pathways, specifically NF-κB/miR488 circuit. Thus, pterostilbene could be an ideal anti-CSC agent in clinical settings.

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