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Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties

Oncogene volume 37, pages 589–600 (2018)Cite this article

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Abstract

Growing evidence indicates that resistin—an obesity-related cytokine—is upregulated in breast cancer patients, yet its impact on breast cancer behavior remains to be ascertained. Similarly, Toll-like receptor 4 (TLR4) has been implicated in breast cancer progression, however, its clinically relevant endogenous ligand remains elusive. In this study, we observed that high serum resistin levels in breast cancer patients positively correlated with tumor stage, size and lymph node metastasis. These findings were replicated in animal models of breast cancer tumorigenesis and metastasis. Resistin was found to promote epithelial–mesenchymal transition and stemness in breast cancer cells—mechanisms critical to tumorigenesis and metastasis—through a TLR4/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and negated by TLR4-specific antibody and antagonist. These findings provide clear evidence that resistin is a clinically relevant endogenous ligand for TLR4, which promotes tumor progression via TLR4/NF-κB/STAT3 signaling, providing insights into a novel therapeutic target in breast cancer.

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Acknowledgements

We thank Dr Tsung-Hsien Chuang and Dr Wen-Chun Hung from National Health Research Institutes, Taiwan, for providing plasmid. This work was supported by Kaohsiung Medical University Hospital (KMUH102-2T07, KMUH103-3R28, KMUH104-4R29); Kaohsiung Medical University (Aim for the Top Journals Grant, KMU-DT105008, KMU-TP104D17); National Health Research Institutes (NHRI-EX104-10212BI); and Ministry of Health and Welfare, Health and welfare surcharge of tobacco products (MOHW105-TDU-B-212-134007) of Taiwan.

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Authors and Affiliations

  1. Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    C-H Wang, P-J Wang, S Lo, Y-C Lee, Y-C Chen, C-H Tsai, C-W Lu, Y-F Yang & S-SF Yuan

  2. Department of Medical Research and Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    C-H Wang, Y-C Chen & S-SF Yuan

  3. Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

    Y-C Hsieh

  4. College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

    S Lo

  5. Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Y-C Lee

  6. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    C-H Tsai & F Ou-Yang

  7. Division of Thoracic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    W-C Chiu

  8. Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    S Chu-Sung Hu

  9. Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    S Chu-Sung Hu

  10. Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan

    C-C Chiu

  11. Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    F Ou-Yang

  12. Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan

    Y-M Wang

  13. Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan

    Y-M Wang

  14. Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    M-F Hou

  15. Department of Surgery, Kaohsiung Municipal Shiao-Kang Hospital, Kaohsiung, Taiwan

    M-F Hou

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Correspondence to S-SF Yuan.

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Wang, CH., Wang, PJ., Hsieh, YC. et al. Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties. Oncogene 37, 589–600 (2018). https://doi.org/10.1038/onc.2017.357

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