Skip to main content

Advertisement

SpringerLink
Log in

NY-BR-1 protein expression in breast carcinoma: a mammary gland differentiation antigen as target for cancer immunotherapy

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

NY-BR-1 is a recently identified differentiation antigen of the mammary gland. To use NY-BR-1 for T-cell-based immunotherapy, analysis of its co-expression with HLA class I antigens is required. In the present tissue microarray study, primary breast cancers (n = 1,444), recurrences (n = 88), lymph node (n = 525) and distant metastases (n = 91) were studied for NY-BR-1 expression using a novel monoclonal antibody. NY-BR-1 expression was compared with prognosis, estrogen receptor, HER2-status, EGFR and HLA class I antigen expression. NY-BR-1 was more frequently expressed in grade 1 (82%) than in grade 2 (69%) and grade 3 (46%) carcinomas (P < 0.0001). Moreover, NY-BR-1 expression correlated directly with estrogen receptor expression (P < 0.0001) and inversely correlated with HER2-status and EGFR expression (P < 0.0001 for both). Considering high expression level of co-expression, 198/1,321 (15%) primary breast carcinomas and 4/65 (6%) distant metastases expressed NY-BR-1 and HLA class I, suggesting that active immunotherapy can be applied to about 10% of breast cancer patients. Survival analysis showed an association of NY-BR-1 expression with better patient outcome (P = 0.015). No difference between NY-BR-1 expression of primary tumors and metastases could be found, indicating that the presence of NY-BR-1 in metastases can be deduced from their corresponding primary. Forty-three paired biopsies taken from patients before and after chemotherapy suggest that NY-BR-1 expression is not influenced by preceding chemotherapy (κ = 0.89, P < 0.0001). In summary, the co-expression of NY-BR-1 with HLA class I antigens and its expression in metastases without modification by chemotherapy suggest that NY-BR-1 targeted immunotherapy represents a viable strategy in addition to other targeted cancer drug therapies of breast cancer.

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

Similar content being viewed by others

References

  1. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672

    Article  PubMed  CAS  Google Scholar 

  2. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684

    Article  PubMed  CAS  Google Scholar 

  3. Jager D, Jager E, Knuth A (2001) Vaccination for malignant melanoma: recent developments. Oncology 60:1–7

    Article  PubMed  CAS  Google Scholar 

  4. Jager E, Ringhoffer M, Altmannsberger M, Arand M, Karbach J, Jager D, Oesch F, Knuth A (1997) Immunoselection in vivo: independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma. Int J Cancer 71:142–147

    Article  PubMed  CAS  Google Scholar 

  5. Jager D, Jager E, Knuth A (2001) Immune responses to tumour antigens: implications for antigen specific immunotherapy of cancer. J Clin Pathol 54:669–674

    PubMed  CAS  Google Scholar 

  6. Li G, Miles A, Line A, Rees RC (2004) Identification of tumour antigens by serological analysis of cDNA expression cloning. Cancer Immunol Immunother 53:139–143

    Article  PubMed  CAS  Google Scholar 

  7. Zendman AJ, Ruiter DJ, Van Muijen GN (2003) Cancer/testis-associated genes: identification, expression profile, and putative function. J Cell Physiol 194:272–288

    Article  PubMed  CAS  Google Scholar 

  8. Jager D, Taverna C, Zippelius A, Knuth A (2004) Identification of tumor antigens as potential target antigens for immunotherapy by serological expression cloning. Cancer Immunol Immunother 53:144–147

    Article  PubMed  Google Scholar 

  9. Jager D, Stockert E, Gure AO, Scanlan MJ, Karbach J, Jager E, Knuth A, Old LJ, Chen YT (2001) Identification of a tissue-specific putative transcription factor in breast tissue by serological screening of a breast cancer library. Cancer Res 61:2055–2061

    PubMed  CAS  Google Scholar 

  10. Jager D, Karbach J, Pauligk C, Seil I, Frei C, Chen YT, Old LJ, Knuth A, Jager E (2005) Humoral and cellular immune response against the breast cancer antigen NY-BR-1: definition of two HLA-A2 restricted peptide epitopes. Cancer Immun 5:11

    PubMed  Google Scholar 

  11. Wang W, Epler J, Salazar LG, Riddell SR (2006) Recognition of breast cancer cells by CD8+ cytotoxic T-cell clones specific for NY-BR-1. Cancer Res 66:6826–6833

    Article  PubMed  CAS  Google Scholar 

  12. Varga Z, Theurillat JP, Filonenko V, Sasse B, Odermatt B, Jungbluth AA, Chen YT, Old LJ, Knuth A, Jager D, Moch H (2006) Preferential nuclear and cytoplasmic NY-BR-1 protein expression in primary breast cancer and lymph node metastases. Clin Cancer Res 12:2745–2751

    Article  PubMed  CAS  Google Scholar 

  13. van Endert PM (1999) Genes regulating MHC class I processing of antigen. Curr Opin Immunol 11:82–88

    Article  PubMed  Google Scholar 

  14. Jager E, Jager D, Knuth A (2002) Clinical cancer vaccine trials. Curr Opin Immunol 14:178–182

    Article  PubMed  CAS  Google Scholar 

  15. Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847

    Article  PubMed  CAS  Google Scholar 

  16. Ellis IO, Schnitt SJ, Sastre-Garau X, Bussolati G, Tavassoli FA, Eusebi V, Peterse JL, Mukai K, Tabar L, Jacquemier J, Cornelisse CJ, Sasco AJ et al (2003) Invasive breast carcinoma. In: Tavassoli FA, Devilee P (eds) Pathology and genetics tumours of the breast and female genital organs. IARC, Lyon, pp 13–48

  17. Varga Z, Caduff R, Pestalozzi B (2005) Stability of the HER2 gene after primary chemotherapy in advanced breast cancer. Virchows Arch 446:136–141

    Article  PubMed  CAS  Google Scholar 

  18. Stam NJ, Spits H, Ploegh HL (1986) Monoclonal antibodies raised against denatured HLA-B locus heavy chains permit biochemical characterization of certain HLA-C locus products. J Immunol 137:2299–2306

    PubMed  CAS  Google Scholar 

  19. Vitale M, Pelusi G, Taroni B, Gobbi G, Micheloni C, Rezzani R, Donato F, Wang X, Ferrone S (2005) HLA class I antigen down-regulation in primary ovary carcinoma lesions: association with disease stage. Clin Cancer Res 11:67–72

    PubMed  CAS  Google Scholar 

  20. Bubendorf L, Nocito A, Moch H, Sauter G (2001) Tissue microarray (TMA) technology: miniaturized pathology archives for high-throughput in situ studies. J Pathol 195:72–79

    Article  PubMed  CAS  Google Scholar 

  21. Simon R, Nocito A, Hubscher T, Bucher C, Torhorst J, Schraml P, Bubendorf L, Mihatsch MM, Moch H, Wilber K, Schotzau A, Kononen J et al (2001) Patterns of her-2/neu amplification and overexpression in primary and metastatic breast cancer. J Natl Cancer Inst 93:1141–1146

    Article  PubMed  CAS  Google Scholar 

  22. Dagrada GP, Mezzelani A, Alasio L, Ruggeri M, Romano R, Pierotti MA, Pilotti S (2003) HER-2/neu assessment in primary chemotherapy treated breast carcinoma: no evidence of gene profile changing. Breast Cancer Res Treat 80:207–214

    Article  PubMed  CAS  Google Scholar 

  23. Johnston SR, Hickish T, Ellis P, Houston S, Kelland L, Dowsett M, Salter J, Michiels B, Perez-Ruixo JJ, Palmer P, Howes A (2003) Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer. J Clin Oncol 21:2492–2499

    Article  PubMed  CAS  Google Scholar 

  24. Gee JM, Robertson JF, Gutteridge E, Ellis IO, Pinder SE, Rubini M, Nicolson RI (2005) Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer. Endocr Relat Cancer 12:99–111

    Article  Google Scholar 

  25. Sauer T, Wiedswang G, Boudjema G, Christensen H, Karesen R (2003) Assessment of HER-2/neu overexpression and/or gene amplification in breast carcinomas: should in situ hybridization be the method of choice? APMIS 111:444–450

    Article  PubMed  CAS  Google Scholar 

  26. Seliger B, Maeurer MJ, Ferrone S (2000) Antigen-processing machinery breakdown and tumor growth. Immunol Today 21:455–64

    Article  PubMed  CAS  Google Scholar 

  27. Hicklin DJ, Marincola FM, Ferrone S (1999) HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story. Mol Med Today 5:178–186

    Article  PubMed  CAS  Google Scholar 

  28. Madjd Z, Spendlove I, Pinder SE, Ellis IO, Durrant LG (2005) Total loss of MHC class I is an independent indicator of good prognosis in breast cancer. Int J Cancer 117:248–255

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The skillful technical assistance of S. Bingge, and S. Behnke is greatly appreciated. The authors wish to thank N. Wey for his help in preparing the photographical illustrations and M. Aerne for supporting database programming. This study was partly supported by grants from LICR/CRI (Cancer Vaccine Collaborative, Cancer Antigen Discovery Collaborative), Claudia von Schilling Foundation for Breast Cancer Research, UBS AG Switzerland (made possible by an anonymous donor), Stiftung für die Forschung in der Onkologie and by PHS grants R01CA 67108 and R01CA 113861 awarded by the National Cancer Institute, DHHS. J. -Ph. Theurillat is supported by a grant form the “Gertrud-Hagmann-Stiftung für Malignomforschung”. The authors do not have potential financial or personal conflicts of interest.

Author information

Author notes

  1. Dirk Jäger

    Present address: Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany

Authors and Affiliations

  1. Institute for Surgical Pathology, Department of Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091, Zurich, Switzerland

    Jean-Philippe Theurillat, Ursina Zürrer-Härdi, Zsuzsanna Varga, Martina Storz & Holger Moch

  2. Molecular Epidemiology Unit/Cancer Registry Zürich, University Hospital of Zurich, Zurich, Switzerland

    Nicole M. Probst-Hensch

  3. Clinic of Oncology, Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland

    Bernhard Pestalozzi, Dirk Jäger & Alexander Knuth

  4. Department of Obstetrics and Gynecology, University Hospital of Zurich, Zurich, Switzerland

    Mathias K. Fehr & Daniel Fink

  5. Division of Biostatistics, University Zurich, Zurich, Switzerland

    Burkhardt Seifert

  6. Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA

    Soldano Ferrone

  7. Ludwig Institute for Cancer Research, New York, USA

    Achim A. Jungbluth

  8. Department of Pathology, Weill Medical College of Cornell University, New York, USA

    Yao-Tseng Chen

Authors
  1. Jean-Philippe Theurillat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ursina Zürrer-Härdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zsuzsanna Varga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martina Storz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nicole M. Probst-Hensch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Burkhardt Seifert
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mathias K. Fehr
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daniel Fink
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Soldano Ferrone
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bernhard Pestalozzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Achim A. Jungbluth
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yao-Tseng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Dirk Jäger
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alexander Knuth
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Holger Moch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean-Philippe Theurillat.

Additional information

Jean-Philippe Theurillat and Ursina Zürrer-Härdi contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Theurillat, JP., Zürrer-Härdi, U., Varga, Z. et al. NY-BR-1 protein expression in breast carcinoma: a mammary gland differentiation antigen as target for cancer immunotherapy. Cancer Immunol Immunother 56, 1723–1731 (2007). https://doi.org/10.1007/s00262-007-0316-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-007-0316-1

Keywords

Search

Navigation