Skip to main content

Advertisement

Springer Nature Link
Log in

Presence of Foxp3 expression in tumor cells predicts better survival in HER2-overexpressing breast cancer patients treated with neoadjuvant chemotherapy

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The Forkhead Box Protein 3 is highly expressed not only in regulatory T cells, but also in tumor cells, acting as a transcriptional repressor of breast oncogenes including HER2. We investigated the prognostic significance of Foxp3 expression in cancer cells in a large cohort of patients with HER2-overexpressing breast carcinoma treated with neoadjuvant chemotherapy. Foxp3-positive tumor cells were detected by immunohistochemistry in 103 patients with primary invasive HER2-overexpressing breast carcinoma, and treated with neoadjuvant chemotherapy, with or without trastuzumab. Kaplan–Meier analysis and Cox regression model were used to assess relapse-free and overall survival, respectively, and according to the presence or the absence of Foxp3 expression in tumor cells. Breast cancer cells were Foxp3+ in 57% of tumors. Foxp3 expression in breast cancer cells was associated with better relapse-free (P = 0.005) and overall survival (P = 0.03). By multivariate analysis, the presence of Foxp3+ tumor cells produced an independent prognostic factor for both better relapse-free (P = 0.006) and overall survival (P = 0.03). These findings indicate that the presence of Foxp3+ tumor cells represents a new independent prognostic factor of improved outcome in HER2-overexpressing breast carcinoma, which could help identify high-risk patients for additional therapies after neoadjuvant chemotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  CAS  PubMed  Google Scholar 

  2. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336

    Article  CAS  PubMed  Google Scholar 

  3. Sakaguchi S, Ono M, Setoguchi R et al (2006) Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212:8–27

    Article  CAS  PubMed  Google Scholar 

  4. Ghiringhelli F, Menard C, Puig PE et al (2007) Metronomic cyclophosphamide regimen selectively depletes CD4+ CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56:641–648

    Article  CAS  PubMed  Google Scholar 

  5. Curiel TJ, Coukos G, Zou L et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  CAS  PubMed  Google Scholar 

  6. Ko HJ, Kim YJ, Kim YS et al (2007) A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer Res 67:7477–7486

    Article  CAS  PubMed  Google Scholar 

  7. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G (2001) Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 193:1303–1310

    Article  CAS  PubMed  Google Scholar 

  8. Ghiringhelli F, Menard C, Martin F, Zitvogel L (2006) The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression. Immunol Rev 214:229–238

    Article  CAS  PubMed  Google Scholar 

  9. Roux S, Apetoh L, Chalmin F et al (2008) CD4+CD25+ tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer. J Clin Investig 118:3751–3761

    Article  CAS  PubMed  Google Scholar 

  10. Karanikas V, Speletas M, Zamanakou M et al (2008) Foxp3 expression in human cancer cells. J Transl Med 6:19

    Article  PubMed  Google Scholar 

  11. Merlo A, Casalini P, Carcangiu ML et al (2009) FOXP3 expression and overall survival in breast cancer. J Clin Oncol 27:1746–1752

    Article  CAS  PubMed  Google Scholar 

  12. Zuo T, Liu R, Zhang H et al (2007) FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2. J Clin Investig 117:3765–3773

    CAS  PubMed  Google Scholar 

  13. Zuo T, Wang L, Morrison C et al (2007) FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 129:1275–1286

    Article  CAS  PubMed  Google Scholar 

  14. Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410

    Article  CAS  PubMed  Google Scholar 

  15. Chevallier B, Roche H, Olivier JP, Chollet P, Hurteloup P (1993) Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate. Am J Clin Oncol 16:223–228

    Article  CAS  PubMed  Google Scholar 

  16. Black MM, Opler SR, Speer FD (1956) Structural representations of tumor-host relationships in gastric carcinoma. Surg Gynecol Obstet 102:599–603

    CAS  PubMed  Google Scholar 

  17. Ladoire S, Arnould L, Apetoh L et al (2008) Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin Cancer Res 14:2413–2420

    Article  CAS  PubMed  Google Scholar 

  18. Coffer PJ, Burgering BM (2004) Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 4:889–899

    Article  CAS  PubMed  Google Scholar 

  19. Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F (2005) Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 65:2457–2464

    Article  CAS  PubMed  Google Scholar 

  20. Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H (2003) Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res 9:4404–4408

    PubMed  Google Scholar 

  21. Bates GJ, Fox SB, Han C et al (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24:5373–5380

    Article  PubMed  Google Scholar 

  22. Hinz S, Pagerols-Raluy L, Oberg HH et al (2007) Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 67:8344–8350

    Article  CAS  PubMed  Google Scholar 

  23. Ebert LM, Tan BS, Browning J et al (2008) The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res 68:3001–3009

    Article  CAS  PubMed  Google Scholar 

  24. Liu Y, Wang Y, Li W, Zheng P (2009) Activating transcription factor 2 and c-Jun-mediated induction of FoxP3 for experimental therapy of mammary tumor in the mouse. Cancer Res 69:5954–5960

    Article  CAS  PubMed  Google Scholar 

  25. Chen GY, Chen C, Wang L, Chang X, Zheng P, Liu Y (2008) Cutting edge: broad expression of the FoxP3 locus in epithelial cells: a caution against early interpretation of fatal inflammatory diseases following in vivo depletion of FoxP3-expressing cells. J Immunol 180:5163–5166

    CAS  PubMed  Google Scholar 

  26. Wang L, Liu R, Li W et al (2009) Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell 16:336–346

    Article  CAS  PubMed  Google Scholar 

  27. Lopes JE, Torgerson TR, Schubert LA et al (2006) Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J Immunol 177:3133–3142

    CAS  PubMed  Google Scholar 

  28. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23:9067–9072

    Article  PubMed  Google Scholar 

  29. Gobert M, Treilleux I, Bendriss-Vermare N et al (2009) Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 69:2000–2009

    Article  CAS  PubMed  Google Scholar 

  30. Nair S, Boczkowski D, Fassnacht M, Pisetsky D, Gilboa E (2007) Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Res 67:371–380

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by Ligue contre le Cancer comité de Côte d’Or, Association pour la Recherche Contre le Cancer (ARC), Fondation de France INSERM AVENIR program and GERTI (Groupe d’Etude et de Recherche en Thérapeutique Innovante). Gregoire Mignot was supported by ARC (Association pour la Recherche contre le Cancer), and Julie Vincent by INCa (Institut National du Cancer).

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Centre Regional de Lutte Contre le Cancer Georges François Leclerc, Dijon, France

    Sylvain Ladoire, Bruno Coudert, Bruno Chauffert, Pierre Fumoleau & François Ghiringhelli

  2. Institut National de la Santé et de la Recherche Médicale, University of Dijon, Avenir Team INSERM. CRI-866, Dijon, France

    Sylvain Ladoire, Grégoire Mignot, Cédric Rébé, Fanny Chalmin, Julie Vincent, Mélanie Bruchard, Bruno Chauffert, François Martin & François Ghiringhelli

  3. Department of Pathology and Molecular Biology, Centre Regional de Lutte Contre le Cancer Georges François Leclerc, Dijon, France

    Sylvain Ladoire, Laurent Arnould, Cédric Rébé & François Ghiringhelli

  4. Faculté de Médecine, Centre Georges François Leclerc, Centre de Recherche INSERM 866, 7 Boulevard Jeanne d’Arc, 21000, Dijon, France

    François Ghiringhelli

Authors
  1. Sylvain Ladoire
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laurent Arnould
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Grégoire Mignot
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bruno Coudert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cédric Rébé
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fanny Chalmin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julie Vincent
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mélanie Bruchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bruno Chauffert
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. François Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Pierre Fumoleau
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. François Ghiringhelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to François Ghiringhelli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ladoire, S., Arnould, L., Mignot, G. et al. Presence of Foxp3 expression in tumor cells predicts better survival in HER2-overexpressing breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 125, 65–72 (2011). https://doi.org/10.1007/s10549-010-0831-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-010-0831-1

Keywords

Search

Navigation