Abstract
Breast cancer (BC) is a health problem worldwide; there is evidence that inflammatory cytokines are increased in BC. Macrophage migration inhibitory factor (MIF) has multiple effects on immune cells, inflammation and cancer. Besides, in previous studies, contradictory and uncertain results have been presented on the implication of Th17 cytokine profile in BC. The aim of this study was to evaluate the plasma levels of MIF and the Th17 cytokine profile in BC and their association with their molecular subtypes and clinical stage. A total of 150 women with BC of Ella Binational Breast Cancer Study and 60 healthy women (HW) were evaluated in cross-sectional study. The molecular subtypes were identified by immunohistochemistry. The plasma levels of MIF were quantified by ELISA and Th17 cytokine profile by multiplex system. MIF and IL-17 were significantly increased in BC versus HW (11.1 vs. 5.2 ng/mL and 14.8 pg/mL vs. 2.5 pg/mL p < 0.001, respectively). Our analysis showed that both MIF and IL-17A were associated with increased risk of breast cancer (OR 3.85 CI 95% 1.98–7.50 and OR 4.51 95% 1.83–11.15, respectively), higher in aggressive subtypes Luminal B, HER2 and TN. Likewise, we observed positive correlation between MIF and IL-17A (p < 0.001). In addition, IL-17E was lower in BC versus HW (p <0.001). Likewise, we observed a positive correlation between MIF and IL-17A (p < 0.001). In conclusion, both MIF and IL-17A were associated with high risk for breast cancer and aggressive molecular subtypes.
Similar content being viewed by others
References
Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.
Karatas F, Erdem GU, Sahin S, et al. Obesity is an independent prognostic factor of decreased pathological complete response to neoadjuvant chemotherapy in breast cancer patients. Breast. 2017;32:237–44. https://doi.org/10.1016/j.breast.2016.05.013.
Eroles P, Bosch A, Alejandro Pérez-Fidalgo J, Lluch A. Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. Cancer Treat Rev. 2012;38(6):698–707. https://doi.org/10.1016/j.ctrv.2011.11.005.
Lukong KE. Understanding breast cancer: the long and winding road. BBA Clin. 2017;7:64–77. https://doi.org/10.1016/j.bbacli.2017.01.001.
Kawczyk-krupka A, Bugaj AM, Latos W, et al. ALA-mediated photodynamic effect on apoptosis induction, and secretion of macrophage migration inhibitory factor (MIF) and of monocyte chemotactic protein (MCP-1), by colon cancer cells in normoxia and in hypoxia-like conditions in vitro. Photodiagnosis Photodyn Ther. 2014;S1572–1000:1–25. https://doi.org/10.1016/j.pdpdt.2014.12.013.
Ballesio L, Gigli S, Di Pastena F, et al. Magnetic resonance imaging tumor regression shrinkage patterns after neoadjuvant chemotherapy in patients with locally advanced breast cancer: correlation with tumor biological subtypes and pathological response after therapy. Tumor Biol. 2017;39(3):1010428317694540.
Dushyanthen S, Beavis PA, Savas P, et al. Relevance of tumor-infiltrating lymphocytes in breast cancer. BMC Med. 2015;13(1):1–13. https://doi.org/10.1186/s12916-015-0431-3.
Pruneri G, Vingiani A, Denkert C. Tumor infiltrating lymphocytes in early breast cancer. Breast. 2018;37:207–14. https://doi.org/10.1016/j.breast.2017.03.010.
Matsumoto H, Koo S, Dent R, Tan PH, Iqbal J. Role of inflammatory infiltrates in triple negative breast cancer. J Clin Pathol. 2015;68(7):506–10. https://doi.org/10.1136/jclinpath-2015-202944.
Agahozo MC, Hammerl D, Debets R, Kok M, van Deurzen CHM. Tumor-infiltrating lymphocytes and ductal carcinoma in situ of the breast: friends or foes? Mod Pathol. 2018;31(7):1012–25.
Thibaudin M, Chaix M, Boidot R, Vegran F, Derangere V, Limagne E, et al. Human ectonucleotidase-expressing CD25(high) Th17 cells accumulate in breast cancer tumors and exert immunosuppressive functions. Oncoimmunology. 2016;5(1):e1055444.
Xu X, Wang B, Ye C, et al. Overexpression of macrophage migration inhibitory factor induces angiogenesis in human breast cancer. Cancer Lett. 2008;261(2):147–57.
Welte T, Zhang XHF. Interleukin-17 could promote breast cancer progression at several stages of the disease. Mediators Inflamm. 2015;2015:1–6.
Richard V, Kindt N, Saussez S. Macrophage migration inhibitory factor involvement in breast cancer (Review). Int J Oncol. 2015;47(5):1627–33.
Calandra T, Roger T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol. 2003;3(10):791–800. http://www.nature.com/doifinder/10.1038/nri1200.
Rendon BE, Willer SS, Zundel W, Mitchell RA. Mechanisms of macrophage migration inhibitory factor (MIF)-dependent tumor microenvironmental adaptation. Exp Mol Pathol. 2009;86(3):180–5. https://doi.org/10.1016/j.yexmp.2009.01.001.
Pawig L, Klasen C, Weber C, Bernhagen J, Noels H. Diversity and inter-connections in the CXCR17 chemokine receptor/ligand family: molecular perspectives. Front Immunol. 2015;6:1–23.
Alampour-Rajabi S, El Bounkari O, Rot A, et al. MIF interacts with CXCR18 to promote receptor internalization, ERK1/2 and ZAP-70 signaling, and lymphocyte chemotaxis. FASEB J. 2015;29(11):4497–511.
Stojanović I, Cvjetićanin T, Lazaroski S, Stošić-Grujičić S, Miljković D. Macrophage migration inhibitory factor stimulates interleukin-17 expression and production in lymph node cells. Immunology. 2009;126(1):74–83.
Guéry L, Hugues S. Th17 cell plasticity and functions in cancer immunity. Biomed Res Int. 2015;2015:314620.
Richard V, Kindt N, Saussez S. Macrophage migration inhibitory factor involvement in breast cancer. Int J Oncol. 2015;47:1627–33.
Gnant M, Thomssen C, Harbeck N. St. Gallen/Vienna 2015: a brief summary of the consensus discussion. Breast care. 2015;10(2):124–30.
Lugrin J, Ding XC, Le Roy D, et al. Histone deacetylase inhibitors repress macrophage migration inhibitory factor (MIF) expression by targeting MIF gene transcription through a local chromatin deacetylation. Biochim Biophys Acta Mol Cell Res. 2009;1793(11):1749–58. https://doi.org/10.1016/j.bbamcr.2009.09.007.
Richard V, Kindt N, Decaestecker C, et al. Involvement of macrophage migration inhibitory factor and its receptor (CD74) in human breast cancer. Oncol Rep. 2014;32(2):523–9.
Velaei K, Samadi N, Barazvan B, Soleimani Rad J. Tumor microenvironment-mediated chemoresistance in breast cancer. Breast. 2016;30:92–100. https://doi.org/10.1016/j.breast.2016.09.002.
Bando H, Matsumoto G, Bando M et al. Expression of macrophage migration inhibitory factor in human breast cancer: association with nodal spread. Jpn J Cancer Res. 2002;93(4):389–96. http://www.ncbi.nlm.nih.gov/pubmed/11985788.
Nobre CCG, Araújo JMG, Fernandes TAA, et al. Macrophage Migration Inhibitory Factor (MIF): biological activities and relation with cancer. Pathol Oncol Res. 2017;23(2):235–44. https://doi.org/10.1007/s12253-016-0138-6.
Choi J, Jung WH, Koo JS. Metabolism-related proteins are differentially expressed according to the molecular subtype of invasive breast cancer defined by surrogate immunohistochemistry. Pathobiology. 2012;80(1):41–52.
Verjans E, Noetzel E, Bektas N, et al. Dual role of macrophage migration inhibitory factor (MIF) in human breast cancer. BMC Cancer. 2009;9:1–18.
Hwang SY, Park S, Kwon Y. Recent therapeutic trends and promising targets in triple negative breast cancer. Pharmacol Ther. 2019 (in Press).
Fabre J, Giustinniani J, Garbar C, et al. The interleukin-17 family of cytokines in breast cancer. Int J Mol Sci. 2018;19(12):3880.
Jankauskas SS, Wong DWL, Bucala R, Djudjaj S, Boor P. Evolving complexity of MIF signaling. Cell Signal. 2019;57:76–88.
Lang T, Lee J, Elgass K, et al. Macrophage migration inhibitory factor is required for NLRP3 inflammasome activation. Nat Commun. 2018;9(1):2223.
Balogh N, Templeton J, Cross V. Macrophage Migration Inhibitory Factor protects cancer cells from immunogenic cell death and impairs anti-tumor immune responses. PLoS ONE. 2018;13(6):e0197702.
Simpson D, Cross V. MIF: metastasis/MDSC-inducing factor? Oncoimmunology. 2013;2(3):e23337.
Umansky V. Myeloid-derived suppressor cells hinder the anti-cancer activity of immune checkpoint inhibitors. Front Immunol. 2018;9:1–9.
Song Y, Yang JM. Role of interleukin (IL)-17 and T-helper (Th)17 cells in cancer. Biochem Biophys Res Commun. 2017;493(1):1–8. https://doi.org/10.1016/j.bbrc.2017.08.109.
Jiang Z, Chen J, Du X, Cheng H, Wang X, Dong C. IL-25 blockade inhibits metastasis in breast cancer. Protein Cell. 2017;8(3):191–201.
Croce M, Rigo V, Ferrini S. IL-21: a pleiotropic cytokine with potential applications in oncology. J Immunol Res. 2015;2015:696578.
Wang L-N, Cui Y-X, Ruge F, Jiang WG. Interleukin 21 and its receptor play a role in proliferation, migration and invasion of breast cancer cells. Cancer Genom Proteom. 2015;12(5):211–21. http://cgp.iiarjournals.org/content/12/5/211.
Ko H, Shen C, Murugan K, et al. Macrophage Migration Inhibitory Factor Acts as the potential target of a Newly synthesized Compound, 1-(9′-methyl-3′-carbazole)-3,4-dihydro-β-carboline. Sci Rep. 2019;9(1):2147.
Acknowledgements
The authors greatly appreciate the important contribution of Rogelio Troyo Sanroman for the statistical analysis.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This study was conducted conforming to the declaration of Helsinki and the research was approved by the ethical investigation, committee from each hospital and Universidad de Guadalajara (CI-9708).
Informed consent
Informed consent was obtained from each participant before enrolling in this study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Avalos-Navarro, G., Muñoz-Valle, J.F., Daneri-Navarro, A. et al. Circulating soluble levels of MIF in women with breast cancer in the molecular subtypes: relationship with Th17 cytokine profile. Clin Exp Med 19, 385–391 (2019). https://doi.org/10.1007/s10238-019-00559-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10238-019-00559-6