Skip to main content

Advertisement

SpringerLink
Log in

Interleukin-34 contributes to poor prognosis in triple-negative breast cancer

  • Rapid Communication
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Triple-negative breast cancer (TNBC) is a subtype characterized by the absence of therapeutic targets. It shows rapid progression, higher relapse, and poor prognosis, so the establishment of an effective therapeutic target is required. We focused on interleukin-34 (IL-34) that is a novel cytokine relating to inflammation and tumorigenesis. It has been reported that IL-34 correlates with poor prognosis of various cancers. In this study, we evaluated the relationship of IL-34 and prognosis in TNBC using human clinical information and mice model. We found that IL-34 was highly expressed in TNBC, and the survival rate in TNBC was significantly lower in patients with high IL-34 expression. Furthermore, multivariate analysis revealed that IL-34 independently affects prognosis. In murine TNBC model, IL-34 deficiency in tumor cells decreased in vivo tumor growth and increased inflammatory cytokine production from macrophages. These results suggest that tumor-derived IL-34 creates a favorable environment for TNBC cells. Thus, we showed a novel pathological role of IL-34 in TNBC and the potential of IL-34 as a therapeutic target for it.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Ghoncheh M, Pournamdar Z, Salehiniya H. Incidence and mortality and epidemiology of breast cancer in the world. Asian Pac J Cancer Prev. 2016;17:43–6.

    Article  Google Scholar 

  2. WHO. Breast cancer. London: World Health Organization; 2019. URL (https://www.who.int/cancer/prevention/diagnosis-screening/breast-cancer/en/)

    Google Scholar 

  3. Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF, et al. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.

    Article  CAS  Google Scholar 

  4. Torres-Adorno AM, Lee J, Kogawa T, Ordentlich P, Tripathy D, Lim B, et al. Histone deacetylase inhibitor enhances the efficacy of MEK inhibitor through NOXA-mediated MCL1 degradation in triple-negative and inflammatory breast cancer. Clin Cancer Res. 2017;23:4780–92.

    Article  CAS  Google Scholar 

  5. Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol. 2006;24:5652–7.

    Article  Google Scholar 

  6. Nedeljković D. Mechanisms of chemotherapy resistance in triple-negative breast cancer—how we can rise to the challenge. Cells. 2019;8:957.

    Article  Google Scholar 

  7. Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E, et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science. 2008;707:807–12.

    Article  Google Scholar 

  8. Baghdadi M, Umeyama Y, Hama N, Kobayashi T, Han N, Wada H, et al. Interleukin-34, a comprehensive review. J Leukoc Biol. 2018;104:931–51.

    Article  CAS  Google Scholar 

  9. Baghdadi M, Wada H, Nakanishi S, Abe H, Han N, Wira EP, et al. Chemotherapy-induced IL34 enhances immunosuppression by tumor-associated macrophages and mediates survival of chemoresistant lung cancer cells. Cancer Res. 2016;76:6030–42.

    Article  CAS  Google Scholar 

  10. Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol. 2008;66:1–9.

    Article  Google Scholar 

  11. Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev. 2006;25:315–22.

    Article  Google Scholar 

  12. Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124:263–6.

    Article  CAS  Google Scholar 

  13. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49–61.

    Article  CAS  Google Scholar 

  14. De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell. 2013;23:277–86.

    Article  Google Scholar 

  15. Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27:462–72.

    Article  CAS  Google Scholar 

  16. Baghdadi M, Endo H, Takano A, Ishikawa K, Kameda Y, Wada H, et al. High co-expression of IL-34 and M-CSF correlates with tumor progression and poor survival in lung cancers. Sci Rep. 2018;8:1–10.

    Article  Google Scholar 

  17. Segaliny AI, Brion R, Mortier E, Maillasson M, Cherel M, Jacques Y, et al. Syndecan-1 regulates the biological activities of interleukin-34. Biochim Biophys Acta Mol Cell Res. 2015;1853:1010–21.

    Article  CAS  Google Scholar 

  18. Zins K, Heller G, Mayerhofer M, Schreiber M, Abraham D. Differential prognostic impact of interleukin-34 mRNA expression and infiltrating immune cell composition in intrinsic breast cancer subtypes. Oncotarget. 2018;9:23126–48.

    Article  Google Scholar 

  19. Kau P, Nagaraja GM, Zheng H, Gizachew D, Galukande M, Krishnan S, et al. A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC-TICs) exhibits similar aggressive phenotype to the human disease. BMC Cancer. 2012;12:120.

    Article  Google Scholar 

  20. Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15:e493–503.

    Article  Google Scholar 

  21. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.

    Article  CAS  Google Scholar 

  22. Watkins LR, Maier SF, Goehler LE. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain. 1995;63:289–302.

    Article  CAS  Google Scholar 

  23. Naugler WE, Karin M. The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med. 2008;14:109–19.

    Article  CAS  Google Scholar 

  24. Mikucki ME, Fisher DT, Ku AW, Appenheimer MM, Muhitch JB, Evans SS. Preconditioning thermal therapy: flipping the switch on IL-6 for anti-tumour immunity. Int J Hyperth. 2013;29:464–73.

    Article  CAS  Google Scholar 

  25. Parameswaran N, Patial S. Tumor necrosis factor-a signaling in macrophages. Crit Rev Eukaryot Gene Expr. 2010;20:87–103.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Japan Agency for Medical Research and Development (AMED; Practical Research for Innovative Cancer Control) (K. Seino). The authors thank Muhammad Baghdadi, Hisataka Sabe, Ari Hashimoto, and Haruka Handa for helpful discussions and advice.

Author information

Authors and Affiliations

  1. Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo, 060-0815, Japan

    Nabeel Kajihara, Fumihito Kitagawa, Takuto Kobayashi, Haruka Wada, Ryo Otsuka & Ken-ichiro Seino

Authors
  1. Nabeel Kajihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fumihito Kitagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takuto Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haruka Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryo Otsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ken-ichiro Seino
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KS and NK designed the study. NK, FK, and TK performed experiments. All authors analyzed data and discussed the results. NK, RO, and KS contributed to manuscript preparation. All authors approved the final version of this manuscript for publication.

Corresponding author

Correspondence to Ken-ichiro Seino.

Ethics declarations

Conflict of interest

The authors declared no potential conflicts of interest.

Ethical approval

All animal procedures were approved by the Animal Care Committee of Hokkaido University (Approval number: 14-0171).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kajihara, N., Kitagawa, F., Kobayashi, T. et al. Interleukin-34 contributes to poor prognosis in triple-negative breast cancer. Breast Cancer 27, 1198–1204 (2020). https://doi.org/10.1007/s12282-020-01123-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-020-01123-x

Keywords

Search

Navigation