Skip to main content

Advertisement

Log in

Regulatory T cells and breast cancer: implications for immunopathogenesis

  • NON-THEMATIC REVIEW
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Current understanding of the role of several cancer risk factors is more comprehensive, as reported for a number of sites, including the brain, colon, breasts, and ovaries. Despite such advances, the incidence of breast cancer continues to increase worldwide. Signals from the microenviroment have a profound influence on the maintenance or progression cancers. Although T cells present the most important immunological response in tumor growth in the early stages of cancer, they become suppressive CD4+ and CD8+ regulatory T cells (Tregs) after chronic stimulation and interactions with tumor cells, thus promoting rather than inhibiting cancer development and progression. Tregs have an important marker protein which is FoxP3, though it does not necessarily confer a Treg phenotype when expressed in CD4+ T lymphocytes. High Treg levels have been reported in peripheral blood, lymph nodes, and tumor specimens from patients with different types of cancer. The precise mechanisms by which Tregs suppress immune cell functions remain unclear, and there are reports of both direct inhibition through cell–cell contact and indirect inhibition through the secretion of anti-inflammatory mediators such as interleukin. In this review, we present the molecular and immunological aspects of Treg cells in the metastasis of breast cancer.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Chu, D., & Lu, J. (2008). Novel therapies in breast cancer: What is new from ASCO 2008. Journal of Hematology Oncology, 1, 1–16.

    Article  Google Scholar 

  2. Kásler, M., Polgár, C., & Fodor, J. (2009). Current status of treatment for early-stage invasive breast cancer. Orvosi Hetilap, 150, 1013–1021.

    Article  PubMed  Google Scholar 

  3. Benz, C. C. (2008). Impact of aging on the biology of breast cancer. Impact of aging on the biology of breast cancer. Critical Reviews in Oncology/Hematology, 66(1), 65–74.

    Article  PubMed  Google Scholar 

  4. Lacroix, M., Toillon, R. A., & Leclercq, G. (2004). Stable ‘portrait’ of breast tumors during progression: Data from biology, pathology and genetics. Endocrine-Related Cancer, 11, 497–522.

    Article  CAS  PubMed  Google Scholar 

  5. Rakha, E. A., El-Sayed, M. E., Reis-Filho, J., & Ellis, I. O. (2009). Patho-biological aspects of basal-like breast cancer. Breast Cancer Research and Treatment, 113, 411–422.

    Article  PubMed  Google Scholar 

  6. Beckmann, M. W., Niederacher, D., Schnürch, H. G., Gusterson, B. A., & Bender, H. G. (1997). Multistep carcinogenesis of breast cancer and tumour heterogeneity. Journal of Molecular Medicine, 75, 429–439.

    Article  CAS  PubMed  Google Scholar 

  7. Perou, C. M., Sorlie, T., Eisen, M. B., van de Rijn, M., Jeffrey, S. S., Rees, C. A., et al. (2000). Molecular portraits of human breast tumours. Nature, 406, 747–752.

    Article  CAS  PubMed  Google Scholar 

  8. Sorlie, T., Perou, C. M., Tibshirani, R., Aas, T., Geisler, S., Johnsen, H., et al. (2001). Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proceedings of the National Academy of Sciences of USA, 98, 10869–10874.

    Article  CAS  Google Scholar 

  9. Sorlie, T., Tibshirani, R., Parker, J., Hastie, T., Marron, J. S., Nobel, A., et al. (2003). Repeated observation of breast tumor subtypes in independent gene expression data sets. Proceedings of the National Academy of Sciences of USA, 100, 8418–8423.

    Article  CAS  Google Scholar 

  10. Bertucci, F., Houlgatte, R., Benziane, A., Granjeaud, S., Adélaïde, J., Tagett, R., et al. (2000). Gene expression profiling of primary breast carcinomas using arrays of candidate genes. Human Molecular Genetics, 9, 2981–2991.

    Article  CAS  PubMed  Google Scholar 

  11. Bergamaschi, A., Kim, Y. H., Wang, P., Sorlie, T., Hernandez-Boussard, T., & Lonning, P. E. (2006). Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes, Chromosomes & Cancer, 45, 1033–1040.

    Article  CAS  Google Scholar 

  12. Chin, K., DeVries, S., Fridlyand, J., Spellman, P. T., Roydasgupta, R., & Kuo, W. L. (2006). Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell, 10, 529–541.

    Article  CAS  PubMed  Google Scholar 

  13. Neve, R. M., Chin, K., Fridlyand, J., Yeh, J., Baehner, F. L., Fevr, T., et al. (2006). A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell, 10, 515–527.

    Article  CAS  PubMed  Google Scholar 

  14. Aoki, M. N., da Silva do Amaral Herrera, A. C., Amarante, M. K., do Val Carneiro, J. L., Fungaro, M. H., & Watanabe, M. A. (2009). CCR5 and p53 codon 72 gene polymorphisms: Implications in breast cancer development. International Journal of Molecular Medicine, 23, 429–435.

    CAS  PubMed  Google Scholar 

  15. 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 

  16. Bernardes, S. S., Borges, I. K., Lima, J. E., de Azevedo Oliveira Milanez, P., Costa, I. C., Felipe, I., et al. (2010). Involvement of regulatory T cells in HIV immunopathogenesis. Current HIV Research, 8, 340–346.

    Article  CAS  PubMed  Google Scholar 

  17. Rosenberg, S. A. (2001). Progress in human tumour immunology and immunotherapy. Nature, 411, 380–384.

    Article  CAS  PubMed  Google Scholar 

  18. Dunn, G. P., Old, L. J., & Schreiber, R. D. (2004). The immunobiology of cancer immunosurveillance and immunoediting. Immunity, 21, 137–148.

    Article  CAS  PubMed  Google Scholar 

  19. Dougan, M., & Dranoff, G. (2009). The immune response to tumors. Current Protocols in Immunology. Chapter 20, Unit 20.11.

  20. Amarante, M. K., & Watanabe, M. A. E. (2009). The possible involvement of virus in breast cancer. Journal of Cancer Research and Clinical Oncology, 135(3), 329–337.

    Article  PubMed  Google Scholar 

  21. Standish, L. J., Sweet, E. S., Novack, J., Wenner, C. A., Bridge, C., Nelson, A., et al. (2008). Breast cancer and the immune system. Journal of the Society for Integrative Oncology, 6, 158–168.

    PubMed  Google Scholar 

  22. Kazbariene, B. (2009). Tumor and immunity. Medicina, 45, 162–167.

    PubMed  Google Scholar 

  23. Tan, T. T., & Coussens, L. M. (2007). Humoral immunity, inflammation and cancer. Current Opinion in Immunology, 19, 209–216.

    Article  CAS  PubMed  Google Scholar 

  24. DeNardo, D. G., & Coussens, L. M. (2007). Inflammation and breast cancer. Balancing immune response: Crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Research, 9, 212.

    Article  PubMed  Google Scholar 

  25. Wang, R. F. (2008). CD8+ regulatory T cells, their suppressive mechanisms, and regulation in cancer. Human Immunology, 69, 811–814.

    Article  CAS  PubMed  Google Scholar 

  26. Sakaguchi, S., Wing, K., & Miyara, M. (2007). Regulatory T cells—A brief history and perspective. European Journal of Immunology, 37(Suppl 1), S116–S123.

    Article  CAS  PubMed  Google Scholar 

  27. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., & Toda, M. (1995). Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. Journal of Immunology, 155(3), 1151–1164.

    CAS  Google Scholar 

  28. Shevach, E. M. (2002). CD4CD25 suppressor T cells: More questions than answers. Nature Reviews. Immunology, 2, 389–400.

    CAS  PubMed  Google Scholar 

  29. Wood, K. J., & Sakaguchi, S. (2003). Regulatory lymphocytes: Regulatory T cells in transplantation tolerance. Nature Review Immunology, 3, 199–210.

    Article  CAS  Google Scholar 

  30. Maloy, K. J., & Powrie, F. (2001). Regulatory T cells in the control of immune pathology. Nature Immunology, 2, 816–822.

    Article  CAS  PubMed  Google Scholar 

  31. Li, M. O., & Flavell, R. A. (2008). TGF-beta: A master of all T cell trades. Cell, 134, 392–404.

    Article  CAS  PubMed  Google Scholar 

  32. Feuerer, M., Hill, J. A., Mathis, M., & Benoist, C. (2009). FoxP3+ regulatory T cells: Differentiation, specification, subphenotypes. Nature Immunolgy, 10, 689–695.

    Article  CAS  Google Scholar 

  33. Curti, A., Pandolfi, S., Valzasina, B., Aluigi, M., Isidori, A., Ferri, E., et al. (2007). Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25S into CD25R T regulatory cells. Blood, 109, 2871–2877.

    CAS  PubMed  Google Scholar 

  34. Thornton, A. M., & Shevach, E. M. (1998). CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. The Journal of Experimental Medicine, 188, 287–296.

    Article  CAS  PubMed  Google Scholar 

  35. Wang, H. Y., Peng, G., Guo, Z., Shevach, E. M., & Wang, R. F. (2005). Recognition of a new ARTC1 peptide ligand uniquely expressed in tumor cells by antigen-specific CD4+ regulatory T cells. Journal of Immunology, 174, 2661–2670.

    CAS  Google Scholar 

  36. Roncarolo, M. G., Gregori, S., Battaglia, M., Bacchetta, R., Fleischhauer, K., & Levings, M. K. (2006). Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunological Reviews, 212, 28–50.

    Article  CAS  PubMed  Google Scholar 

  37. Weiner, H. L. (2001). Induction and mechanism of action of transforming growth factor beta-secreting Th3 regulatory cells. Immunological Reviews, 182, 207–214.

    Article  CAS  PubMed  Google Scholar 

  38. Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003). FoxP3 programs the development and function of CD4+CD25 regulatory T cells. Nature Immunology, 4, 330–336.

    Article  CAS  PubMed  Google Scholar 

  39. Bacchetta, R., Passerini, L., Gambineri, E., Daí, M., Allan, S. E., Perroni, L., et al. (2006). Defective regulatory and effector T cell functions in patients with FoxP3 mutations. The Journal of Clinical Investigation, 116, 1713–1722.

    Article  CAS  PubMed  Google Scholar 

  40. Gavin, M. A., Torgerson, T. R., Houston, E., DeRoos, P., Ho, W. Y., Stray-Pedersen, A., et al. (2006). Single-cell analysis of normal and FOXP3-mutant human T cells: FoxP3 expression without regulatory T cell development. Proceedings of the National Academy of Sciences of the USA, 103, 6659–6664.

    Article  CAS  PubMed  Google Scholar 

  41. Roncador, G., Brown, P. J., Maestre, L., Hue, S., Martínez-Torrecuadrada, J. L., Ling, K. L., et al. (2005). Analysis of FoxP3 protein expression in human CD4(+)CD25(+) regulatory T cells at the single-cell level. European Journal of Immunology, 35, 1681–1691.

    Article  CAS  PubMed  Google Scholar 

  42. Li, B., Saouaf, S. J., Samanta, A., Shen, Y., Hancock, W. W., & Greene, M. I. (2007). Biochemistry and therapeutic implications of mechanisms involved in FoxP3 activity in immune suppression. Current Opinion in Immunology, 19, 583–588.

    Article  CAS  PubMed  Google Scholar 

  43. Wu, Y., Borde, M., Heissmeyer, V., Feuerer, M., Lapan, A. D., Stroud, J. C., et al. (2006). FoxP3 controls regulatory T cell function through cooperation with NFAT. Cell, 126, 375–387.

    Article  CAS  PubMed  Google Scholar 

  44. Cruvinel, W. M., Mesquita, D., Jr., Araújo, J. A. P., Salmazi, K. C., Kállas, E. G., Andrade, L. E. C., et al. (2008). Natural regulatory T cells in rheumatic diseases. Revista Brasileira de Reumatologia, 48, 342–355.

    Article  Google Scholar 

  45. Lin, H., Sun, X. F., Zhen, Z. J., Xia, Y., Ling, J. Y., Huang, H. Q., et al. (2009). Correlation between peripheral blood CD4+CD25highCD127low regulatory T cell and clinical characteristics of patients with non-Hodgkin’s lymphoma. Ai Zheng, 28(11), 1186–1192.

    PubMed  Google Scholar 

  46. Whiteside, T. L. (2006). Immune suppression in cancer: Effects on immune cells, mechanisms and future therapeutic intervention. Seminars in Cancer Biology, 16(1), 3–15.

    Article  CAS  PubMed  Google Scholar 

  47. Mansfield, A. S., Heikkila, P. S., Vaara, A. T., von Smitten, K. A., Vakkila, J. M., & Leidenius, M. H. (2009). Simultaneous FoxP3 and IDO expression is associated with sentinel lymph node metastases in breast cancer. BMC Cancer, 9, 231.

    Article  PubMed  Google Scholar 

  48. Zhou, L., Lopes, J. E., Chong, M. M. W., Ivanov, I. I., Min, R., Victora, G. D., et al. (2008). TGF-β-induced FoxP3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature, 453, 236–240.

    Article  CAS  PubMed  Google Scholar 

  49. Voo, K. S., Wang, Y. H., Santori, F. R., Boggiano, C., Wang, Y. H., Arima, K., et al. (2009). Identification of IL-17-producing FoxP3+ regulatory T cells in humans. Proceedings of the National Academy of Sciences of USA, 106, 4793–4798.

    Article  CAS  Google Scholar 

  50. Beyer, M., Kochanek, M., Giese, T., Endl, E., Weihrauch, M. R., Knolle, P. A., et al. (2006). In vivo peripheral expansion of naive CD4+CD25highFoxP3+ regulatory T cells in patients with multiple myeloma. Blood, 107, 3940–3949.

    Article  CAS  PubMed  Google Scholar 

  51. Wang, H. Y., & Wang, R. F. (2007). Regulatory T cells and cancer. Current Opinion in Immunology, 19, 217–223.

    Article  CAS  PubMed  Google Scholar 

  52. Liu, Z., Kim, J. H., Falo, L. D., Jr., & You, Z. (2009). Tumor regulatory T cells potently abrogate antitumor immunity. Journal of Immunology, 182, 6160–6167.

    Article  CAS  Google Scholar 

  53. Konwar, R., Chaudhary, P., Kumar, S., Mishra, D., Chattopadhyay, N., & Bid, H. K. (2009). Breast cancer risks associated with polymorphisms of IL-1RN and IL-4 gene in Indian women. Oncology Research, 17, 367–372.

    Article  PubMed  Google Scholar 

  54. Zhou, X., Bailey-Bucktrout, S., Jeker, L. T., & Bluestone, J. A. (2009). Plasticity of CD4(+) FoxP3(+) T cells. Current Opinion in Immunology, 21, 281–285.

    Article  CAS  PubMed  Google Scholar 

  55. Kosmaczewska, A., Ciszak, L., Potoczek, S., & Frydecka, I. (2008). The significance of Treg cells in defective tumor immunity. Archivum Immunologiae et Therapie Experimentalis, 56, 181–191.

    Article  CAS  Google Scholar 

  56. Gupta, S., Joshi, K., Wig, J. D., & Arora, S. K. (2007). Intratumoral FoxP3 expression in infiltrating breast carcinoma: Its association with clinicopathologic parameters and angiogenesis. Acta Oncológica, 46, 792–797.

    Article  CAS  PubMed  Google Scholar 

  57. Karanikas, V., Speletas, M., Zamanakou, M., Kalala, F., Loules, G., Kerenidi, T., et al. (2008). FoxP3 expression in human cancer cells. Journal of Translational Medicine, 6, 19.

    Article  PubMed  Google Scholar 

  58. Liu, L., Wu, G., Yao, J. X., Liu, L., Wu, G., Yao, J. X., et al. (2008). CD4+CD25high regulatory cells in peripheral blood of cancer patients. Neuro Endocrinology Letters, 29, 240–245.

    PubMed  Google Scholar 

  59. Bates, G. J., Fox, S. B., Han, C., Leek, R. D., Garcia, J. F., Harris, A. L., et al. (2006). Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. Journal of Clinical Oncology, 24, 5373–5380.

    Article  PubMed  Google Scholar 

  60. Liu, Y., & Zheng, P. (2007). FoxP3 and breast cancer: Implications for therapy and diagnosis. Pharmacogenomics, 8, 1485–1487.

    Article  CAS  PubMed  Google Scholar 

  61. Zuo, T., Wang, L., Morrison, C., Chang, X., Zhang, H., Li, W., et al. (2007). FoxP3 is an X-linked breast cancer suppressor gene and an important repressor of HER-2/ErbB2 oncogene. Cell, 129, 1275–1286.

    Article  CAS  PubMed  Google Scholar 

  62. Ohara, M., Yamaguchi, Y., Matsuura, K., Murakami, S., Arihiro, K., & Okada, M. (2009). Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunology Immunotherapy: CII, 58, 441–447.

    Article  CAS  Google Scholar 

  63. Ladoire, S., Arnould, L., Mignot, G., Coudert, B., Rébé, C., Chalmin, F., et al. (2010). Presence of FoxP3 expression in tumor cells predicts better survival in HER2-overexpressing breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Research and Treatment, doi:10.1007/s10549-010-0831-1

  64. Selenko-Gebauer, N., Majdic, O., Szekeres, A., Höfler, G., Guthann, E., Korthäuer, U., et al. (2003). B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. Journal of Immunology, 170, 3637–3644.

    CAS  Google Scholar 

  65. Iwai, Y., Ishida, M., Tanaka, Y., Okazaki, T., Honjo, T., & Minato, N. (2002). Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proceedings of the National Academy of Sciences of the USA, 99, 12293–12297.

    Article  CAS  PubMed  Google Scholar 

  66. Ghebeh, H., Barhoush, E., Tulbah, A., Elkum, N., Al-Tweigeri, T., & Dermime, S. (2008). FoxP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy. BMC Cancer, 23, 8–57.

    Google Scholar 

  67. Berger, C. L., Tigelaar, R., Cohen, J., Mariwalla, K., Trinh, J., Wang, N., et al. (2005). Cutaneous T cell lymphoma: Malignant proliferation of T regulatory cells. Blood, 105, 1640–1647.

    Article  CAS  PubMed  Google Scholar 

  68. Karube, K., Ohshima, K., Tsuchiya, T., Yamaguchi, T., Kawano, R., Suzumiya, J., et al. (2004). Expression of FoxP3, a key molecule in CD4+CD25+ regulatory T cells, in adult T cell leukaemia/lymphoma cells. British Journal Haematology, 126, 81–84.

    Article  CAS  Google Scholar 

  69. Liyanage, U. K., Moore, T. T., Joo, H. G., Tanaka, Y., Herrmann, V., Doherty, G., et al. (2002). Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. Journal of Immunology, 169, 2756–2761.

    CAS  Google Scholar 

  70. Perez, S. A., Karamouzis, M. V., Skarlos, D. V., Ardavanis, A., Sotiriadou, N. N., Iliopoulou, E. G., et al. (2007). CD4+CD25+ regulatory T-cell frequency in HER-2/neu (HER)-positive and HER-negative advanced-stage breast cancer patients. Clinical Cancer Research, 13, 2714–2721.

    Article  CAS  PubMed  Google Scholar 

  71. Wolf, A. M., Wolf, D., Steurer, M., Gastl, G., Gunsilius, E., Grubeck-Loebenstein, B., et al. (2003). Increase of regulatory T cells in the peripheral blood of cancer patients. Clinical Cancer Research, 9(2), 606–612.

    PubMed  Google Scholar 

  72. Bi, Y., Wei, L., Mao, H. T., Zhang, L., & Zuo, W. S. (2008). Expressions of Fas, CTLA-4 and RhoBTB2 genes in breast carcinoma and their relationship with clinicopathological factors. Zhonghua ZhongLiu Za Zhi, 30, 749–753.

    CAS  Google Scholar 

  73. Jaberipour, M., Habibagahi, M., Hosseini, A., Habibabad, S. R., Talei, A., & Ghaderi, A. (2010). Increased CTLA-4 and FOXP3 transcripts in peripheral blood mononuclear cells of patients with breast cancer. Pathology Oncology Research, doi:10.1007/s12253-010-9256-8

  74. Raskin, L., Rennert, G., & Gruber, S. B. (2009). FoxP3 germline polymorphisms are not associated with risk of breast cancer. Cancer Genetics and Cytogenetics, 190, 40–42.

    Article  CAS  PubMed  Google Scholar 

  75. Fidler, I. J. (2003). The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nature Reviews. Cancer, 3, 453–458.

    Article  CAS  PubMed  Google Scholar 

  76. Gupta, G. P., & Massagué, J. (2006). Cancer metastasis: Building a framework. Cell, 127, 679–695.

    Article  CAS  PubMed  Google Scholar 

  77. Audia, S., Nicolas, A., Cathelin, D., Larmonier, N., Ferrand, C., Foucher, P., et al. (2007). Increase of CD4+ CD25++ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: A phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+CD25+ T lymphocytes. Clinical and Experimental Immunology, 150(3), 523–530.

    Article  CAS  PubMed  Google Scholar 

  78. Rech, A. J., Mick, R., Kaplan, D. E., Chang, K. M., Domchek, S. M., & Vonderheide, R. H. (2010). Homeostasis of peripheral FoxP3(+) CD4 (+) regulatory T cells in patients with early and late stage breast cancer. Cancer Immunology, Immunotherapy, 59(4), 599–607.

    Article  CAS  PubMed  Google Scholar 

  79. Aruga, T., Suzuki, E., Saji, S., Horiguchi, S., Horiguchi, K., Sekine, S., et al. (2009). A low number of tumor-infiltrating FOXP3-positive cells during primary systemic chemotherapy correlates with favorable anti-tumor response in patients with breast cancer. Oncology Reports, 22, 273–278.

    CAS  PubMed  Google Scholar 

  80. Merlo, A., Casalini, P., Carcangiu, M. L., Malventano, C., Triulzi, T., Mènard, S., et al. (2009). FoxP3 expression and overall survival in breast cancer. Journal of Clinical Oncology, 27, 1746–1752.

    Article  CAS  PubMed  Google Scholar 

  81. Carneiro, J. L. V., Nixdorf, S. L., Mantovani, M. S., da Silva do Amaral Herrera, A. C., Aoki, M. N., Amarante, M. K., et al. (2009). Plasma malondialdehyde levels and CXCR4 expression in peripheral blood cells of breast cancer patients. Journal of Cancer Research and Clinical Oncology, 135, 997–1004.

    Article  CAS  Google Scholar 

  82. Müller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature, 410(6824), 50–56.

    Article  PubMed  Google Scholar 

  83. Shimizu, Y., Dobashi, K., Imai, H., Sunaga, N., Ono, A., Sano, T., et al. (2009). CXCR4+FOXP3+CD25+ lymphocytes accumulate in CXCL12-expressing malignant pleural mesothelioma. International Journal of Immunopathology and Pharmacology, 22, 43–51.

    CAS  PubMed  Google Scholar 

  84. Ishida, T., & Ueda, R. (2006). CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Science, 97(11), 1139–1146.

    Article  CAS  PubMed  Google Scholar 

  85. Mougiakakos, D., Choudhury, A., Lladser, A., Kiessling, R., & Johansson, C. C. (2010). Regulatory T cells in cancer. Advances in Cancer Research, 107, 57–117.

    Article  CAS  PubMed  Google Scholar 

  86. Xu, L., Xu, W., Qiu, S., & Xiong, S. (2010). Enrichment of CCR6(+)Foxp3(+) regulatory T cells in the tumor mass correlates with impaired CD8(+) T cell function and poor prognosis of breast cancer. Clinical Immunology, 135, 466–475.

    Article  CAS  PubMed  Google Scholar 

  87. Tannock, I. F., Hill, R. P., Bristow, R. G., & Harrington, L. (2005). The basic science of oncology. New York: McGraw-Hill.

    Google Scholar 

  88. Nguyen, D. X., & Massagué, J. (2007). Genetic determinants of cancer metastasis. Nature Reviews Genetics, 8, 341–352.

    Article  CAS  PubMed  Google Scholar 

  89. Alam, S. M., Clark, J. S., George, W. D., & Campbell, A. M. (1993). Altered lymphocyte populations in tumour invaded nodes of breast cancer patients. Immunology Letters, 35(3), 229–234.

    Article  CAS  PubMed  Google Scholar 

  90. Nakamura, R., Sakakibara, M., Nagashima, T., Sangai, T., Arai, M., Fujimori, T., et al. (2009). Accumulation of regulatory T cells in sentinel lymph nodes is a prognostic predictor in patients with node-negative breast cancer. European Journal of Cancer, 45, 2123–2131.

    Article  CAS  PubMed  Google Scholar 

  91. Matsuura, K., Yamaguchi, Y., Osaki, A., Ohara, M., Okita, R., Emi, A., et al. (2009). FoxP3 expression of micrometastasis-positive sentinel nodes in breast cancer patients. Oncology Reports, 22(5), 1181–1187.

    Article  CAS  PubMed  Google Scholar 

  92. Akhurst, R. J., & Derynck, R. (2001). TGF-beta signalling in cancer—A double-edged sword. Trends in Cell Biology, 11, S44–S51.

    CAS  PubMed  Google Scholar 

  93. Kalluri, R., & Zeisberg, M. (2006). Fibroblasts in cancer. Nature Reviews Cancer, 6, 392–401.

    Article  CAS  PubMed  Google Scholar 

  94. Pollard, J. W. (2004). Tumour-educated macrophages promote tumor progression and metastasis. Nature Reviews. Cancer, 4, 71–78.

    Article  CAS  PubMed  Google Scholar 

  95. Wels, J., Kaplan, R. N., Rafii, S., & Lyden, D. (2008). Migratory neighbors and distant invaders: Tumor-associated niche cells. Genes & Development, 22, 559–574.

    Article  CAS  Google Scholar 

  96. Gobert, M., Treilleux, I., Bendriss-Vermare, N., Bachelot, T., Goddard-Leon, S., Arfi, V., 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 Research, 69(5), 2000–2009.

    Article  CAS  PubMed  Google Scholar 

  97. Zheng, Y., & Rudensky, A. Y. (2007). Foxp3 in control of the regulatory T cell lineage. Nature Immunology, 8, 457–462.

    Article  CAS  PubMed  Google Scholar 

  98. Kodama, J., Hasengaowa, Kusumoto, T., Seki, N., Matsuo, T., Ojima, Y., et al. (2007). Association of CXCR4 and CCR7 chemokine receptorexpression and lymph node metastasis in human cervical cancer. Annals of Oncology, 18, 70–76.

    Article  CAS  PubMed  Google Scholar 

  99. Pitkin, L., Luangdilok, S., Corbishley, C., Wilson, P. O., Dalton, P., Bray, D., et al. (2007). Expression of CC chemokine receptor 7 in tonsillar cancer predicts cervical nodal metastasis, systemic relapse and survival. British Journal of Cancer, 97, 670–677.

    Article  CAS  PubMed  Google Scholar 

  100. Lu, H. (2009). FoxP3 expression and prognosis: Role of both the tumor and T cells. Journal of Clinical Oncology, 27(11), 1735–1736.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), the Fundação Araucária of Paraná, and the Coordenadoria de Pós-Graduação, Londrina State University, PROPPG-UEL. The entire article was revised by a British-born scientific text editor.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maria Angelica Ehara Watanabe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watanabe, M.A.E., Oda, J.M.M., Amarante, M.K. et al. Regulatory T cells and breast cancer: implications for immunopathogenesis. Cancer Metastasis Rev 29, 569–579 (2010). https://doi.org/10.1007/s10555-010-9247-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-010-9247-y

Keywords

Navigation