Document Type : Original Research


1 Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran

2 Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

3 Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran


Background and Objective: S100A8/A9 is a heterodimer calcium-binding protein which is involved in tumor cell proliferation, adhesion and invasion, and is proposed as a biomarker for better diagnosis and prognosis in many cancers. The aim of this study was to evaluate the simultaneous serum-based level of S100A8/A9 and CA15-3 as well-illustrated cancer biomarkers, as well as their prognostic value in breast cancer patients and healthy matched controls.
Material and Methods: Thirty breast cancer patients at different stages of disease and healthy matched controls with no history of inflammatory, autoimmune diseases, or cancer, were enrolled in the study. The levels of S100A8/A9 and CA15-3 were assessed serologically using the Enzyme-linked immunosorbent assay (ELISA) method, and the relevance of these markers with patients’ clinicopathological features were subsequently assessed.
 Results: Based on our data, the serum levels of both S100A8/A9 and CA15-3 were significantly higher in patients compared to the healthy controls, and thus positively correlated with tumor size. Also, statistical analysis shows that the serum level of S100A8/A9 has 100% specificity and sensitivity (AUC = 1.00, 95% CI) for the diagnosis of breast cancer patients.
Conclusion: According to our data as well as other observations, the S100A8/A9 heterodimer can be considered as a potential biomarker for the proper diagnosis and prognosis of breast cancer.


  1. Mancuso MR, Massarweh SA. Endocrine therapy and strategies to overcome therapeutic resistance in breast cancer. Current problems in cancer. 2016. /j.currpro blcancer.2016.09.001 PMID:27839747
  2. O'Connor JP, Aboagye EO, Adams JE, Aerts HJ, Barrington SF, Beer AJ, et al. Imaging biomarker roadmap for cancer studies. Nature reviews Clinical oncology. 2016.
  3. Duffy MJ, Evoy D, McDermott EW. CA 15-3: uses and limitation as a biomarker for breast cancer. Clinica chimica acta; international journal of clinical chemistry. 2010;411(23-24):1869-74. 10.08.039 PMID:20816948
  4. Rahn JJ, Chow JW, Horne GJ, Mah BK, Emerman JT, Hoffman P, et al. MUC1 mediates transendothelial migration in vitro by ligating endothelial cell ICAM-1. Clinical & experimental metastasis. 2005;22(6):475-83.
  5. Kufe DW. Mucins in cancer: function, prognosis and therapy. Nature reviews Cancer. 2009;9(12):874-85.
    PMID:19935676 PMCid:PMC2951677
  6. Duffy MJ, Shering S, Sherry F, McDermott E, O'Higgins N. CA 15-3: a prognostic marker in breast cancer. The International journal of biological markers. 2000;15(4):330-3.
  7. Nakatani Y, Yamazaki M, Chazin WJ, Yui S. Regulation of S100A8/A9 (calprotectin) binding to tumor cells by zinc ion and its implication for apoptosis-inducing activity. Mediators of inflammation. 2005; 2005 (5):280-92.
    PMid:16258195 PMCid:PMC1279038
  8. Lim SY, Yuzhalin AE, Gordon-Weeks AN, Muschel RJ. Tumor-infiltrating monocytes/ macrophages promote tumor invasion and migration by upregulating S100A8 and S100A9 expression in cancer cells. Oncogene. 2016;35(44):5735-45.
    PMID:27086923 PMCid:PMC4961254
  9. Khammanivong A, Sorenson BS, Ross KF, Dickerson EB, Hasina R, Lingen MW, et al. Involvement of calprotectin (S100A8/A9) in molecular pathways associated with HNSCC. Oncotarget. 2016;7(12):14029-47.
    PMID:26883112 PMCid:PMC4924696
  10. Duan L, Wu R, Ye L, Wang H, Yang X, Zhang Y, et al. S100A8 and S100A9 are associated with colorectal carcinoma progression and contribute to colorectal carcinoma cell survival and migration via Wnt/beta-catenin pathway. PloS one. 2013;8(4):e62092. 10.1371/journal.pone.0062092 PMID:23637971 PMCid:PMC3637369
  11. Moris D, Spartalis E, Angelou A, Margonis GA, Papalambros A, Petrou A, et al. The value of calprotectin S100A8/A9 complex as a biomarker in colorectal cancer: A systematic review. Journal of BUON. official journal of the Balkan Union of Oncology. 2016;21(4):859-66.
  12. Bansal N, Gupta AK, Gupta A, Sankhwar SN, Mahdi AA. Serum-based protein biomarkers of bladder cancer: A pre- and post-operative evaluation. Journal of pharmaceutical and biomedical analysis. 2016;124 :22-5.
  13. Teoh SL, Das S. Tumour biology of obesity-related cancers: understanding the molecular concept for better diagnosis and treatment. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2016.
  14. Tavakoli Yaraki M, Karami Tehrani F. Apoptosis Induced by 13-S-hydroxyoctadecadienoic acid in the Breast Cancer Cell Lines, MCF-7 and MDA-MB-231. Iranian journal of basic medical sciences. 2013;16(4):661-9.
  15. Kim HJ, Kang HJ, Lee H, Lee ST, Yu MH, Kim H, et al. Identification of S100A8 and S100A9 as serological markers for colorectal cancer. Journal of proteome research. 2009;8(3):1368-79.
  16. Bao YI, Wang A, Mo J. S100A8/A9 is associated with estrogen receptor loss in breast cancer. Oncology letters. 2016;11(3):1936-42.
    PMID:26998104 PMCid:PMC4774479
  17. Yin C, Li H, Zhang B, Liu Y, Lu G, Lu S, et al. RAGE-binding S100A8/A9 promotes the migration and invasion of human breast cancer cells through actin polymerization and epithelial-mesenchymal transition. Breast cancer research and treatment. 2013;142(2):297-309. s10549-013-2737-1 PMID:24177755
  18. Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell. 2012;150(1):165-78.
    PMID:22770218 PMCid:PMC3528019
  19. Rodriguez-Barrueco R, Yu J, Saucedo-Cuevas LP, Olivan M, Llobet-Navas D, Putcha P, et al. Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers. Genes & development. 2015;29(15):1631-48.
    PMID:26227964 PMCid:PMC4536311
  20. Li C, Li S, Jia C, Yang L, Song Z, Wang Y. Low concentration of S100A8/9 promotes angiogenesis-related activity of vascular endothelial cells: bridges among inflammation, angiogenesis, and tumorigenesis? Mediators of inflammation. 2012;2012:248574.
    PMID:22685372 PMCid:PMC3363068
  21. Duffy MJ, Duggan C, Keane R, Hill AD, McDermott E, Crown J, et al. High preoperative CA 15-3 concentrations predict adverse outcome in node-negative and node-positive breast cancer: study of 600 patients with histologically confirmed breast cancer. Clinical chemistry. 2004;50(3):559-63. 10.1373/clinchem.2003.025288 PMID:14726467