Tumor Biology

, Volume 35, Issue 1, pp 277–286 | Cite as

YKL-40 expression could be a poor prognostic marker in the breast cancer tissue

  • Eun Joo Kang
  • Hoiseon Jung
  • Ok Hee Woo
  • Kyong Hwa Park
  • Sang Uk Woo
  • Dae Sik Yang
  • Ae-Ree Kim
  • Jae-Bok Lee
  • Yeul Hong Kim
  • Jun Suk Kim
  • Jae Hong Seo
Research Article


YKL-40 is a glycoprotein involved in cellular growth, migration, and the inflammatory process. Elevation in serum levels of YKL-40 has been associated with worse prognosis in various cancers, including breast cancer. Given that the clinical significance of YKL-40 expression in breast cancer tissue is unclear, we aimed to determine the prognostic value of YKL-40 expression in breast cancer tissue using immunohistochemistry. We performed tissue microarray (TMA) analysis of 425 breast cancer tissues collected during operation. Immunohistochemical staining was performed to measure expression of YKL-40 and several breast cancer biomarkers, such as aldehyde dehyadrogenase1, TGF-beta, and Gli-1 as well as hormonal receptor and Her-2/neu status. Statistical analysis of the relationship of YKL-40 expression with clinicopathological characteristics was performed for 390 TMA samples. YKL-40 was expressed to varying degrees in 84.9 % of breast cancer tissues. YKL-40 expression was correlated with estrogen receptor and progesterone receptor negativity and was positively correlated with TGF-beta and Gli-1 expression. Strong YKL-40 expression was associated with a larger proportion of Her-2/neu-enriched and basal-like tumors. The results of this study demonstrate that YKL-40 expression in breast cancer tissues is associated with hormone receptor negativity and Her-2/neu-enriched molecular subtypes of breast cancer, and therefore could be considered a poor prognostic predictor.


YKL-40 Breast cancer Prognostic marker 


Conflicts of interest



  1. 1.
    Knight 3rd WA, Osborne CK, Yochmowitz MG, McGuire WL. Steroid hormone receptors in the management of human breast cancer. Ann Clin Res. 1980;12:202–7.PubMedGoogle Scholar
  2. 2.
    Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Johansen JS, Jensen HS, Price PA. A new biochemical marker for joint injury. Analysis of YKL-40 in serum and synovial fluid. Br J Rheumatol. 1993;32:949–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Hakala BE, White C, Recklies AD. Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem. 1993;268:25803–10.PubMedGoogle Scholar
  5. 5.
    Renkema GH, Boot RG, Au FL, et al. Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. Eur J Biochem. 1998;251:504–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Fusetti F, Pijning T, Kalk KH, et al. Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39. J Biol Chem. 2003;278:37753–60.PubMedCrossRefGoogle Scholar
  7. 7.
    Johansen JS, Williamson MK, Rice JS, Price PA. Identification of proteins secreted by human osteoblastic cells in culture. J Bone Miner Res. 1992;7:501–12.PubMedCrossRefGoogle Scholar
  8. 8.
    Junker N, Johansen JS, Hansen LT, et al. Regulation of YKL-40 expression during genotoxic or microenvironmental stress in human glioblastoma cells. Cancer Sci. 2005;96:183–90.PubMedCrossRefGoogle Scholar
  9. 9.
    Volck B, Johansen JS, Stoltenberg M, et al. Studies on YKL-40 in knee joints of patients with rheumatoid arthritis and osteoarthritis. Involvement of YKL-40 in the joint pathology. Osteoarthr Cartil. 2001;9:203–14.PubMedCrossRefGoogle Scholar
  10. 10.
    Boot RG, van Achterberg TA, van Aken BE, et al. Strong induction of members of the chitinase family of proteins in atherosclerosis: chitotriosidase and human cartilage gp-39 expressed in lesion macrophages. Arterioscler Thromb Vasc Biol. 1999;19:687–94.PubMedCrossRefGoogle Scholar
  11. 11.
    Johansen JS, Baslund B, Garbarsch C, et al. YKL-40 in giant cells and macrophages from patients with giant cell arteritis. Arthritis Rheum. 1999;42:2624–30.PubMedCrossRefGoogle Scholar
  12. 12.
    Letuve S, Kozhich A, Arouche N, et al. YKL-40 is elevated in patients with chronic obstructive pulmonary disease and activates alveolar macrophages. J Immunol. 2008;181:5167–73.PubMedGoogle Scholar
  13. 13.
    Rathcke CN, Persson F, Tarnow L, et al. YKL-40, a marker of inflammation and endothelial dysfunction, is elevated in patients with type 1 diabetes and increases with levels of albuminuria. Diabetes Care. 2009;32:323–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Chupp GL, Lee CG, Jarjour N, et al. A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med. 2007;357:2016–27.PubMedCrossRefGoogle Scholar
  15. 15.
    Recklies AD, White C, Ling H. The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways. Biochem J. 2002;365:119–26.PubMedCrossRefGoogle Scholar
  16. 16.
    Malinda KM, Ponce L, Kleinman HK, et al. Gp38k, a protein synthesized by vascular smooth muscle cells, stimulates directional migration of human umbilical vein endothelial cells. Exp Cell Res. 1999;250:168–73.PubMedCrossRefGoogle Scholar
  17. 17.
    Nishikawa KC, Millis AJ. gp38k (CHI3L1) is a novel adhesion and migration factor for vascular cells. Exp Cell Res. 2003;287:79–87.PubMedCrossRefGoogle Scholar
  18. 18.
    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Johansen JS, Christensen IJ, Riisbro R, et al. High serum YKL-40 levels in patients with primary breast cancer is related to short recurrence free survival. Breast Cancer Res Treat. 2003;80:15–21.PubMedCrossRefGoogle Scholar
  20. 20.
    Johansen JS, Cintin C, Jorgensen M, et al. Serum YKL-40: a new potential marker of prognosis and location of metastases of patients with recurrent breast cancer. Eur J Cancer. 1995;31A:1437–42.PubMedCrossRefGoogle Scholar
  21. 21.
    Cintin C, Johansen JS, Christensen IJ, et al. High serum YKL-40 level after surgery for colorectal carcinoma is related to short survival. Cancer. 2002;95:267–74.PubMedCrossRefGoogle Scholar
  22. 22.
    Jensen BV, Johansen JS, Price PA. High levels of serum HER-2/neu and YKL-40 independently reflect aggressiveness of metastatic breast cancer. Clin Cancer Res. 2003;9:4423–34.PubMedGoogle Scholar
  23. 23.
    Dehn H, Hogdall EV, Johansen JS, et al. Plasma YKL-40, as a prognostic tumor marker in recurrent ovarian cancer. Acta Obstet Gynecol Scand. 2003;82:287–93.PubMedCrossRefGoogle Scholar
  24. 24.
    Johansen JS, Drivsholm L, Price PA, Christensen IJ. High serum YKL-40 level in patients with small cell lung cancer is related to early death. Lung Cancer. 2004;46:333–40.PubMedCrossRefGoogle Scholar
  25. 25.
    Schmidt H, Johansen JS, Gehl J, et al. Elevated serum level of YKL-40 is an independent prognostic factor for poor survival in patients with metastatic melanoma. Cancer. 2006;106:1130–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Roslind A, Johansen JS, Junker N, et al. YKL-40 expression in benign and malignant lesions of the breast: a methodologic study. Appl Immunohistochem Mol Morphol. 2007;15:371–81.PubMedCrossRefGoogle Scholar
  27. 27.
    Xiao XQ, Hassanein T, Li QF, et al. YKL-40 expression in human hepatocellular carcinoma: a potential biomarker? Hepatobiliary Pancreat Dis Int. 2011;10:605–10.PubMedCrossRefGoogle Scholar
  28. 28.
    Antonelli M, Buttarelli FR, Arcella A, et al. Prognostic significance of histological grading, p53 status, YKL-40 expression, and IDH1 mutations in pediatric high-grade gliomas. J Neurooncol. 2010;99:209–15.PubMedCrossRefGoogle Scholar
  29. 29.
    ten Haaf A, Bektas N, von Serenyi S, et al. Expression of the glioma-associated oncogene homolog (GLI) 1 in human breast cancer is associated with unfavourable overall survival. BMC Cancer. 2009;9:298.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Yoshioka T, Umekita Y, Ohi Y, et al. Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node-positive breast cancers: a long-term follow-up study. Histopathology. 2011;58:608–16.PubMedCrossRefGoogle Scholar
  31. 31.
    Desruisseau S, Palmari J, Giusti C, et al. Determination of TGFbeta1 protein level in human primary breast cancers and its relationship with survival. Br J Cancer. 2006;94:239–46.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131:18–43.PubMedGoogle Scholar
  33. 33.
    Kim SH, Das K, Noreen S, et al. Prognostic implications of immunohistochemically detected YKL-40 expression in breast cancer. World J Surg Oncol. 2007;5:17.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Roslind A, Knoop AS, Jensen MB, et al. YKL-40 protein expression is not a prognostic marker in patients with primary breast cancer. Breast Cancer Res Treat. 2008;112:275–85.PubMedCrossRefGoogle Scholar
  35. 35.
    Shao R, Cao QJ, Arenas RB, et al. Breast cancer expression of YKL-40 correlates with tumour grade, poor differentiation, and other cancer markers. Br J Cancer. 2011;105:1203–9.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Yamac D, Ozturk B, Coskun U, et al. Serum YKL-40 levels as a prognostic factor in patients with locally advanced breast cancer. Adv Ther. 2008;25:801–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Imamura T, Hikita A, Inoue Y. The roles of TGF-beta signaling in carcinogenesis and breast cancer metastasis. Breast Cancer. 2012;19:118–24.PubMedCrossRefGoogle Scholar
  38. 38.
    Yoo YA, Kang MH, Kim JS, Oh SC. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis. 2008;29:480–90.PubMedCrossRefGoogle Scholar
  39. 39.
    Dennler S, Andre J, Alexaki I, et al. Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 2007;67:6981–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Faibish M, Francescone R, Bentley B, et al. A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers. Mol Cancer Ther. 2011;10:742–51.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Coskun U, Yamac D, Gulbahar O, et al. Locally advanced breast carcinoma treated with neoadjuvant chemotherapy: are the changes in serum levels of YKL-40, MMP-2 and MMP-9 correlated with tumor response? Neoplasma. 2007;54:348–52.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Eun Joo Kang
    • 1
  • Hoiseon Jung
    • 2
  • Ok Hee Woo
    • 3
  • Kyong Hwa Park
    • 1
  • Sang Uk Woo
    • 4
  • Dae Sik Yang
    • 5
  • Ae-Ree Kim
    • 6
  • Jae-Bok Lee
    • 4
  • Yeul Hong Kim
    • 1
  • Jun Suk Kim
    • 1
  • Jae Hong Seo
    • 1
  1. 1.Division of Medical Oncology, Department of Internal MedicineKorea UniversitySeoulKorea
  2. 2.Department of PathologyKwandong UniversitySeoulKorea
  3. 3.Department of Diagnostic RadiologyKorea UniversitySeoulKorea
  4. 4.Department of SurgeryKorea UniversitySeoulKorea
  5. 5.Department of Radiation OncologyKorea UniversitySeoulKorea
  6. 6.Department of PathologyKorea UniversitySeoulKorea

Personalised recommendations