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Cytoplasmic expression of the JM403 antigen GlcA-GlcNH +3 on heparan sulfate glycosaminoglycan in mammary carcinomas—a novel proliferative biomarker for breast cancers with high malignancy

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Abstract

The expressions of heparan sulfate glycosaminoglycans (HSGAGs) in breast carcinoma specimens from 60 patients were immunohistochemically investigated using monoclonal antibodies (mAbs) that recognized different epitopes of the glycan structure. Cytoplasmic expression of GlcA-GlcNH +3 on HSGAG was detected in carcinomas at high frequency (58.3%) using mAb JM403, whereas it was almost undetectable in normal breast ducts. This cytoplasmic expression was confirmed using confocal laser scanning microscopy. The expression of JM403 antigen in invasive carcinomas significantly correlated with nuclear atypia score (p = 0.0004), mitotic counts score (p = 0.0018), nuclear grade (p = 0.0061) and the incidence of metastasis to axillary lymph nodes (p = 0.0061). Furthermore, its expression was significantly correlated with the Ki67-labeling index in 55 invasive carcinomas (p < 0.05) as well as in 26 non-invasive carcinomas (5 non-invasive carcinomas and 21 non-invasive carcinomas that were observed in individual invasive carcinomas) (p < 0.005). Interestingly, the JM403 antigen GlcA-GlcNH +3 was also expressed in the cytoplasm of normal crypt epithelial cells where Ki67 protein was expressed in the cell nuclei in the proliferative compartment of the human small intestines. To date, HSGAGs have generally been found to exist on cell surface membranes and in extracellular matrices as components of HS proteoglycans, and the negatively-charged sulfated domains on HSGAGs are considered to be important for their functions. However, our present findings indicate that the cytoplasmic expression of the JM403 antigen GlcA-GlcNH +3 on positively charged, non-sulfated HSGAG may be involved in cell proliferation and associated with increased degrees of malignancy. The unordinary carbohydrate antigen of GlcA-GlcNH +3 on HSGAGs recognized by mAb JM403 may represent a novel proliferative biomarker for highly malignant mammary carcinomas.

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Abbreviations

CLSM:

confocal laser scanning microscopy/microscope

ER:

estrogen receptor

PgR:

progesterone receptor

HER2:

Human epidermal growth factor receptor type 2

References

  1. Kannagi, R., Hakomori, S.: A guide to monoclonal antibodies directed to glycotopes. Adv. Exp. Med. Biol. 491, 587–630 (2001)

    CAS  PubMed  Google Scholar 

  2. Kannagi, R., Izawa, M., Koike, T., Miyazaki, K., Kimura, N.: Carbohydrate-mediated cell adhesion in cancer metastasis and angiogenesis. Cancer Sci. 95, 377–384 (2004)

    Article  CAS  PubMed  Google Scholar 

  3. Sasisekharan, R., Shriver, Z., Venkataraman, G., Narayanasami, U.: Roles of heparan-sulphate glycosaminoglycans in cancer. Nat. Rev. Cancer 2, 521–528 (2002)

    Article  CAS  PubMed  Google Scholar 

  4. Koo, C.Y., Bay, B.H., Lui, P.C., Tse, G.M., Tan, P.H., Yip, G.W.: Immunohistochemical expression of heparan sulfate correlates with stromal cell proliferation in breast phyllodes tumors. Mod. Pathol. 19, 1344–1350 (2006)

    Article  CAS  PubMed  Google Scholar 

  5. Stanley, M.J., Stanley, M.W., Sanderson, R.D., Zera, R.: Syndecan-1 expression is induced in the stroma of infiltrating breast carcinoma. Am. J. Clin. Pathol. 112, 377–83 (1999)

    CAS  PubMed  Google Scholar 

  6. Matsuda, K., Maruyama, H., Guo, F., Kleeff, J., Itakura, J., Matsumoto, Y., Lander, A.D., Korc, M.: Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells. Cancer Res. 61, 5562–5569 (2001)

    CAS  PubMed  Google Scholar 

  7. Yamauchi, N., Watanabe, A., Hishinuma, M., Ohashi, K., Midorikawa, Y., Morishita, Y., Niki, T., Shibahara, J., Mori, M., Makuuchi, M., Hippo, Y., Kodama, T., Iwanari, H., Aburatani, H., Fukayama, M.: The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma. Mod. Pathol. 18, 1591–1598 (2005)

    CAS  PubMed  Google Scholar 

  8. Wang, X.Y., Degos, F., Dubois, S., Tessiore, S., Allegretta, M., Guttmann, R.D., Jothy, S., Belghiti, J., Bedossa, P., Paradis, V.: Glypican-3 expression in hepatocellular tumors: diagnostic value for preneoplastic lesions and hepatocellular carcinomas. Hum. Pathol. 37, 1435–1441 (2006)

    Article  CAS  PubMed  Google Scholar 

  9. Götte, M., Yip, G.W.: Heparanase, hyaluronan, and CD44 in cancers: a breast carcinoma perspective. Cancer Res. 66, 10233–10237 (2006)

    Article  PubMed  Google Scholar 

  10. McKenzie, E.A.: Heparanase: a target for drug discovery in cancer and inflammation. Br. J. Pharmacol. 151, 1–14 (2007)

    Article  CAS  PubMed  Google Scholar 

  11. Kreuger, J., Spillmann, D., Li, J.P., Lindahl, U.: Interactions between heparan sulfate and proteins: the concept of specificity. J. Cell Biol. 174, 323–327 (2006)

    Article  CAS  PubMed  Google Scholar 

  12. Bishop, J.R., Schuksz, M., Esko, J.D.: Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 446, 1030–1037 (2007)

    Article  CAS  PubMed  Google Scholar 

  13. Jang-Lee, J., North, S.J., Sutton-Smith, M., Goldberg, D., Panico, M., Morris, H., Haslam, S., Dell, A.: Glycomic profiling of cells and tissues by mass spectrometry: fingerprinting and sequencing methodologies. Methods Enzymol. 415, 59–86 (2006)

    Article  CAS  PubMed  Google Scholar 

  14. Hirabayashi, J.: Concept, strategy and realization of lectin-based glycan profiling. J. Biochem. 144, 139–147 (2008)

    Article  CAS  PubMed  Google Scholar 

  15. Ashikari-Hada, S., Habuchi, H., Kariya, Y., Itoh, N., Reddi, A.H., Kimata, K.: Characterization of growth factor-binding structures in heparin/heparan sulfate using an octasaccharide library. J. Biol. Chem. 279, 12346–12354 (2004)

    Article  CAS  PubMed  Google Scholar 

  16. Ferrara, N.: Vascular endothelial growth factor: basic science and clinical progress. Endocr. Rev. 25, 581–611 (2004)

    Article  CAS  PubMed  Google Scholar 

  17. Mauri, D., Polyzos, N.P., Salanti, G., Pavlidis, N., Ioannidis, J.P.: Multiple-treatments meta-analysis of chemotherapy and targeted therapies in advanced breast cancer. J. Natl. Cancer Inst. 100, 1780–1791 (2008)

    Article  CAS  PubMed  Google Scholar 

  18. The Japanese Breast Cancer Society: Histological classification. Breast Cancer 12, S12–S14 (2005)

    Article  Google Scholar 

  19. Tsuda, H., Akiyama, F., Kurosumi, M., Sakamoto, G., Watanabe, T.: Establishment of histological criteria for high-risk node-negative breast carcinoma for a multi-institutional randomized clinical trial of adjuvant therapy. Jpn. J. Clin. Oncol. 28, 486–491 (1998)

    Article  CAS  PubMed  Google Scholar 

  20. van den Born, J., Gunnarsson, K., Bakker, M.A., Kjellén, L., Kusche-Gullberg, M., Maccarana, M., Berden, J.H., Lindahl, U.: Presence of N-unsubstituted glucosamine units in native heparan sulfate revealed by a monoclonal antibody. J. Biol. Chem. 270, 31303–31309 (1995)

    Article  PubMed  Google Scholar 

  21. David, G., Bai, X.M., Van der Schueren, B., Cassiman, J.J., Van den Berghe, H.: Developmental changes in heparan sulfate expression: in situ detection with mAbs. J. Cell. Biol. 119, 961–975 (1992)

    Article  CAS  PubMed  Google Scholar 

  22. Suzuki, K., Yamamoto, K., Kariya, Y., Maeda, H., Ishimaru, T., Miyaura, S., Fujii, M., Yusa, A., Joo, E.J., Kimata, K., Kannagi, R., Kim, Y.S., Kyogashima, M.: Generation and characterization of a series of monoclonal antibodies that specifically recognize [HexA(+/-2 S)-GlcNAc]n epitopes in heparan sulfate. Glycoconj. J. 25, 703–712 (2008)

    Article  CAS  PubMed  Google Scholar 

  23. Cattoretti, G., Becker, M.H., Key, G., Duchrow, M., Schlüter, C., Galle, J., Gerdes, J.: Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J. Pathol. 168, 357–363 (1992)

    Article  CAS  PubMed  Google Scholar 

  24. Ghosh, S., Sullivan, C.A., Zerkowski, M.P., Molinaro, A.M., Rimm, D.L., Camp, R.L., Chung, G.G.: High levels of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome in breast cancer. Hum. Pathol. 39, 1835–1843 (2008)

    Article  CAS  PubMed  Google Scholar 

  25. Kolset, S.O., Tveit, H.: Serglycin-structure and biology. Cell. Mol. Life Sci. 65, 1073–1085 (2008)

    Article  CAS  PubMed  Google Scholar 

  26. Westling, C., Lindahl, U.: Location of N-unsubstituted glucosamine residues in heparan sulfate. J. Biol. Chem. 277, 49247–49255 (2002)

    Article  CAS  PubMed  Google Scholar 

  27. Martellini, J.A., Cole, A.L., Venkataraman, N., Quinn, G.A., Svoboda, P., Gangrade, B.K., Pohl, J., Sørensen, O.E., Cole, A.M.: Cationic polypeptides contribute to the anti-HIV-1 activity of human seminal plasma. FASEB J. 23, 3609–3618 (2009)

    Article  CAS  PubMed  Google Scholar 

  28. Gugliucci, A.: Polyamines as clinical laboratory tools. Clin. Chim. Acta. 344, 23–35 (2004)

    Article  CAS  PubMed  Google Scholar 

  29. Hirabayashi, Y., Igarashi, Y., Merrill Jr., A.H.: Sphingolipids synthesis, transport and cellular signaling. In: Hirabayashi, Y., et al. (eds.) Sphingolipid biology, pp. 3–22. Springer, Tokyo (2006)

    Chapter  Google Scholar 

  30. van den Born, J., Salmivirta, K., Henttinen, T., Ostman, N., Ishimaru, T., Miyaura, S., Yoshida, K., Salmivirta, M.: Novel heparan sulfate structures revealed by monoclonal antibodies. J. Biol. Chem. 280, 20516–20523 (2005)

    Article  PubMed  Google Scholar 

  31. Goldhirsch, A., Ingle, J.N., Gelber, R.D., Coates, A.S., Thürlimann, B., Senn, H.J.; Panel members: Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009. Ann. Oncol. 20, 1319–1329 (2009)

    Article  CAS  PubMed  Google Scholar 

  32. Jalava, P., Kuopio, T., Juntti-Patinen, L., Kotkansalo, T., Kronqvist, P., Collan, Y.: Ki67 immunohistochemistry: a valuable marker in prognostication but with a risk of misclassification: proliferation subgroups formed based on Ki67 immunoreactivity and standardized mitotic index. Histopathology 48, 674–682 (2006)

    Article  CAS  PubMed  Google Scholar 

  33. Urruticoechea, A., Smith, I.E., Dowsett, M.: Proliferation marker Ki-67 in early breast cancer. J. Clin. Oncol. 23, 7212–7220 (2005)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Prof. Yeong Shik Kim for donating acharan, (IdoA-GlcNAc)n. We also thank Ms. Mineko Izawa for advice on immunohistochemical techniques. This work was supported by grants from the Aichi Cancer Research Foundation and the Japan Society for the Promotion of Science (22570150), and by a special research fund from Seikagaku Biobusiness Corporation.

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Authors and Affiliations

  1. Division of Molecular Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan

    Masahiro Fujii, Akiko Yusa, Reiji Kannagi & Mamoru Kyogashima

  2. Division of Surgical Oncology, Department of Surgery Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Masahiro Fujii, Yukihiro Yokoyama, Toshio Kokuryo, Nobuyuki Tsunoda, Koji Oda & Masato Nagino

  3. Department of Breast Oncology, Aichi Cancer Center Aichi Hospital, 18 Kuriyado, Kakemachi, Okazaki, 444-0011, Japan

    Masahiro Fujii & Koji Oda

  4. Seikagaku Biobusiness Corporation, Research Institutes, 3-1253 Tateno, Higashiyamato, Tokyo, 207-0021, Japan

    Tsuyoshi Ishimaru

  5. Department of Pathology, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Yoshie Shimoyama

  6. Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan

    Hirotoshi Utsunomiya

  7. Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan

    Hiroji Iwata

  8. Cell Science, Teaching and Research Support Center, School of Medicine, Tokai University, 143 Shimokasuya, Isehara, 259-1193, Japan

    Yoshiko Itoh & Johbu Itoh

  9. Department of Oncology, Nagoya City University Graduate School of Pharmaceutical Science, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, 464-8603, Japan

    Mamoru Kyogashima

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  1. Masahiro Fujii
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  2. Akiko Yusa
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Correspondence to Mamoru Kyogashima.

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Fujii, M., Yusa, A., Yokoyama, Y. et al. Cytoplasmic expression of the JM403 antigen GlcA-GlcNH +3 on heparan sulfate glycosaminoglycan in mammary carcinomas—a novel proliferative biomarker for breast cancers with high malignancy. Glycoconj J 27, 661–672 (2010). https://doi.org/10.1007/s10719-010-9311-4

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