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MxA expression is associated with tumor-infiltrating lymphocytes and is a prognostic factor in triple-negative breast cancer

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Abstract

Interferons (IFNs) play an important role in tumor–immune system interactions. As one of the main mediators of IFNs, myxovirus resistance A (MxA) is upregulated in various cancers. However, the exact role of MxA in breast cancer is not fully understood. As part of the immune response to tumors, tumor-infiltrating lymphocytes (TILs) have prognostic significance in breast cancer. The aim of our present study was to examine the relationship between MxA and immune system components, including the amount of TILs and human leukocyte antigen (HLA) expression, in breast cancer. TILs, MxA expression, HLA intensity, and clinicopathological factors were retrospectively analyzed in 688 patients with primary breast cancer between 1993 and 1998 and in 705 patients with triple-negative breast cancer (TNBC) between 2004 and 2011. MxA expression was higher in TNBC tumors than in other subtypes. High MxA levels were associated with a higher histologic grade, abundant TILs, and stronger HLA-ABC expression in both the TNBC subtype within the consecutive breast cancer cohort and the validation TNBC cohort. MxA expression showed a significant positive correlation with TILs, the number of CD8+ cells, and the number of CD69+ cells in the validation TNBC cohort. High MxA levels and abundant TILs were found to be independent prognostic factors for disease-free survival in patients with TNBC. These results indicate that MxA expression is closely related to TILs in TNBC and, along with TILs, provides prognostic information after chemotherapy in patients with TNBC.

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References

  1. McNamara KM, Yoda T, Takagi K, Miki Y, Suzuki T, Sasano H (2013) Androgen receptor in triple negative breast cancer. J Steroid Biochem Mol Biol 133:66–76

    Article  CAS  PubMed  Google Scholar 

  2. Perez-Balaguer A, Ortiz-Martinez F, Garcia-Martinez A, Pomares-Navarro C, Lerma E, Peiro G (2015) FOXA2 mRNA expression is associated with relapse in patients with Triple-Negative/Basal-like breast carcinoma. Breast Cancer Res Treat 153(2):465–474

    Article  CAS  PubMed  Google Scholar 

  3. Krishnan SR, Nair BC, Sareddy GR, Roy SS, Natarajan M, Suzuki T, Peng Y et al (2015) Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells. Breast Cancer Res Treat 150(3):487–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. van Rooijen JM, Stutvoet TS, Schroder CP, de Vries EG (2015) Immunotherapeutic options on the horizon in breast cancer treatment. Pharmacol Ther 156:90–101

    Article  PubMed  Google Scholar 

  5. Hu X, Stern HM, Ge L, O’Brien C, Haydu L, Honchell CD, Haverty PM et al (2009) Genetic alterations and oncogenic pathways associated with breast cancer subtypes. Mol Cancer Res 7(4):511–522

    Article  CAS  PubMed  Google Scholar 

  6. Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G et al (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486(7403):395–399

    CAS  PubMed  Google Scholar 

  7. Disis ML, Stanton SE (2015) Triple-negative breast cancer: immune modulation as the new treatment paradigm. Am Soc Clin Oncol Educ Book 35:e25–e30

    Article  Google Scholar 

  8. Andreopoulou E, Schweber SJ, Sparano JA, McDaid HM (2015) Therapies for triple negative breast cancer. Expert Opin Pharmacother 16(7):983–998

    Article  CAS  PubMed  Google Scholar 

  9. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G et al (2013) Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 31(7):860–867

    Article  CAS  PubMed  Google Scholar 

  10. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S et al (2014) Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 32(27):2959–2966

    Article  PubMed  PubMed Central  Google Scholar 

  11. Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J et al (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28(1):105–113

    Article  CAS  PubMed  Google Scholar 

  12. Lee HJ, Seo JY, Ahn JH, Ahn SH, Gong G (2013) Tumor-associated lymphocytes predict response to neoadjuvant chemotherapy in breast cancer patients. J Breast Cancer 16(1):32–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Choi HJ, Lui A, Ogony J, Jan R, Sims PJ, Lewis-Wambi J (2015) Targeting interferon response genes sensitizes aromatase inhibitor resistant breast cancer cells to estrogen-induced cell death. Breast Cancer Res 17:6

    Article  PubMed  PubMed Central  Google Scholar 

  14. Liu YP, Suksanpaisan L, Steele MB, Russell SJ, Peng KW (2013) Induction of antiviral genes by the tumor microenvironment confers resistance to virotherapy. Sci Rep 3:2375

    PubMed  PubMed Central  Google Scholar 

  15. Callari M, Musella V, Di Buduo E, Sensi M, Miodini P, Dugo M, Orlandi R et al (2014) Subtype-dependent prognostic relevance of an interferon-induced pathway metagene in node-negative breast cancer. Mol Oncol 8(7):1278–1289

    Article  CAS  PubMed  Google Scholar 

  16. Hu JL, Hua YJ, Chen Y, Yu B, Gao S (2015) Structural analysis of tumor-related single amino acid mutations in human MxA protein. Chin J Cancer 34(3):55

    Article  PubMed Central  Google Scholar 

  17. Lee HJ, Park IA, Song IH, Shin SJ, Kim JY, Yu JH, Gong G (2015) Tertiary lymphoid structures: prognostic significance and relationship with tumour-infiltrating lymphocytes in triple-negative breast cancer. J Clin Pathol. doi:10.1136/jclinpath-2015-203089

    PubMed Central  Google Scholar 

  18. Lee HJ, Kim JY, Park IA, Song IH, Yu JH, Ahn JH, Gong G (2015) Prognostic significance of tumor-infiltrating lymphocytes and the tertiary lymphoid structures in HER2-positive breast cancer treated with adjuvant Trastuzumab. Am J Clin Pathol 144(2):278–288

    Article  PubMed  Google Scholar 

  19. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCIEWGoCD (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23(36):9067–9072

    Article  PubMed  Google Scholar 

  20. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S et al (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26(2):259–271

    Article  CAS  PubMed  Google Scholar 

  21. Lakhani SREI, Schnitt SJ, Tan PH, van de Vijver MJ (eds) (2012) WHO classification of tumours of the breast. International Agency for Research on Cancer, Lyon

    Google Scholar 

  22. Lee HJ, Seo AN, Park SY, Kim JY, Park JY, Yu JH, Ahn JH et al (2014) Low prognostic implication of fibroblast growth factor family activation in triple-negative breast cancer subsets. Ann Surg Oncol 21(5):1561–1568

    Article  PubMed  Google Scholar 

  23. Hammond ME, Hayes DF, Wolff AC, Mangu PB, Temin S (2010) American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract 6(4):195–197

    Article  PubMed  PubMed Central  Google Scholar 

  24. Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17(5):1474–1481

    CAS  PubMed  Google Scholar 

  25. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC et al (2014) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med 138(2):241–256

    Article  PubMed  PubMed Central  Google Scholar 

  26. Torigoe T, Asanuma H, Nakazawa E, Tamura Y, Hirohashi Y, Yamamoto E, Kanaseki T et al (2012) Establishment of a monoclonal anti-pan HLA class I antibody suitable for immunostaining of formalin-fixed tissue: unusually high frequency of down-regulation in breast cancer tissues. Pathol Int 62(5):303–308

    Article  CAS  PubMed  Google Scholar 

  27. Haller O, Staeheli P, Schwemmle M, Kochs G (2015) Mx GTPases: dynamin-like antiviral machines of innate immunity. Trends Microbiol 23(3):154–163

    Article  CAS  PubMed  Google Scholar 

  28. Welsh RM, Bahl K, Marshall HD, Urban SL (2012) Type 1 interferons and antiviral CD8 T-cell responses. PLoS Pathog 8(1):e1002352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Paschen A, Mendez RM, Jimenez P, Sucker A, Ruiz-Cabello F, Song M, Garrido F et al (2003) Complete loss of HLA class I antigen expression on melanoma cells: a result of successive mutational events. Int J Cancer 103(6):759–767

    Article  CAS  PubMed  Google Scholar 

  30. Lindahl P, Gresser I, Leary P, Tovey M (1976) Interferon treatment of mice: enhanced expression of histocompatibility antigens on lymphoid cells. Proc Natl Acad Sci USA 73(4):1284–1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ismail A, Yusuf N (2014) Type I interferons: key players in normal skin and select cutaneous malignancies. Dermatol Res Pract 2014:847545

    PubMed  PubMed Central  Google Scholar 

  32. Tsavaris N, Baxevanis C, Kosmidis P, Papamichael M (1996) The prognostic significance of immune changes in patients with renal cancer, melanoma and colorectal cancer, treated with interferon alpha 2b. Cancer Immunol Immunother 43(2):94–102

    Article  CAS  PubMed  Google Scholar 

  33. Chaganty BKR, Lu Y, Somanchi SS, Lee DA, Fan Z (2015) Trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules through engagement of natural killer cells and stimulation of IFN-γ secretion. Oncoimmunology. doi:10.1080/2162402X.2015.1100790

    Google Scholar 

  34. Zhang H, Angelopoulos N, Xu Y, Grothey A, Nunes J, Stebbing J, Giamas G (2015) Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer. Breast Cancer Res Treat 151(3):555–568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liikanen I, Monsurro V, Ahtiainen L, Raki M, Hakkarainen T, Diaconu I, Escutenaire S et al (2011) Induction of interferon pathways mediates in vivo resistance to oncolytic adenovirus. Mol Ther 19(10):1858–1866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee SH, Vidal SM (2002) Functional diversity of Mx proteins: variations on a theme of host resistance to infection. Genome Res 12(4):527–530

    Article  CAS  PubMed  Google Scholar 

  37. Croner RS, Sturzl M, Rau TT, Metodieva G, Geppert CI, Naschberger E, Lausen B et al (2014) Quantitative proteome profiling of lymph node-positive vs. -negative colorectal carcinomas pinpoints MX1 as a marker for lymph node metastasis. Int J Cancer 135(12):2878–2886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Brown SG, Knowell AE, Hunt A, Patel D, Bhosle S, Chaudhary J (2015) Interferon inducible antiviral MxA is inversely associated with prostate cancer and regulates cell cycle, invasion and Docetaxel induced apoptosis. Prostate 75(3):266–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot DP, Adam J, Vitale I et al (2014) Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med 20(11):1301–1309

    Article  CAS  PubMed  Google Scholar 

  40. Duarte CW, Willey CD, Zhi D, Cui X, Harris JJ, Vaughan LK, Mehta T et al (2012) Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner. PLoS One 7(1):e29653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by a grant (HI15C0708) of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea.

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Correspondence to Gyungyub Gong.

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All authors declare no conflicts of interest.

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Young-Ae Kim and Hee Jin Lee have contributed equally to this work.

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Kim, YA., Lee, H.J., Heo, SH. et al. MxA expression is associated with tumor-infiltrating lymphocytes and is a prognostic factor in triple-negative breast cancer. Breast Cancer Res Treat 156, 597–606 (2016). https://doi.org/10.1007/s10549-016-3786-z

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  • DOI: https://doi.org/10.1007/s10549-016-3786-z

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