DOI QR코드

DOI QR Code

Association between p53 Expression and Amount of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer

  • Lee, Miseon (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Park, In Ah (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Heo, Sun-Hee (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Young-Ae (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Gong, Gyungyub (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Hee Jin (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2018.11.20
  • Accepted : 2019.02.08
  • Published : 2019.05.15

Abstract

Background: Most triple-negative breast cancers (TNBCs) have a high histologic grade, are associated with high endoplasmic stress, and possess a high frequency of TP53 mutations. TP53 missense mutations lead to the production of mutant p53 protein and usually show high levels of p53 protein expression. Tumor-infiltrating lymphocytes (TILs) accumulate as part of the anti-tumor immune response and have a strong prognostic and predictive significance in TNBC. We aimed to elucidate the association between p53 expression and the amount of TILs in TNBC. Methods: In 678 TNBC patients, we evaluated TIL levels and expression of endoplasmic stress molecules. Immunohistochemical examination of p53 protein expression was categorized into three groups: no, low, and high expression. Results: No, low, and high p53 expression was identified in 44.1% (n=299), 20.1% (n=136), and 35.8% (n=243) of patients, respectively. Patients with high p53 expression showed high histologic grade (p<.001), high TIL levels (p=.009), and high expression of endoplasmic reticulum stress-associated molecules (p-eIF2a, p=.013; XBP1, p=.007), compared to patients with low p53 expression. There was no significant difference in disease-free (p=.406) or overall survival rates (p=.444) among the three p53 expression groups. Conclusions: High p53 expression is associated with increased expression of endoplasmic reticulum stress molecules and TIL influx.

References

  1. Yamashita N, Kondo M, Zhao S, et al. Picrasidine G decreases viability of MDA-MB 468 EGFR-overexpressing triple-negative breast cancer cells through inhibition of EGFR/STAT3 signaling pathway. Bioorg Med Chem Lett 2017; 27: 2608-12. https://doi.org/10.1016/j.bmcl.2017.03.061
  2. Yadav BS, Chanana P, Jhamb S. Biomarkers in triple negative breast cancer: a review. World J Clin Oncol 2015; 6: 252-63. https://doi.org/10.5306/wjco.v6.i6.252
  3. van Rooijen JM, Stutvoet TS, Schroder CP, de Vries EG. Immunotherapeutic options on the horizon in breast cancer treatment. Pharmacol Ther 2015; 156: 90-101. https://doi.org/10.1016/j.pharmthera.2015.09.003
  4. Kim JY, Heo SH, Song IH, et al. Activation of the PERK-eIF2alpha pathway is associated with tumor-infiltrating lymphocytes in HER2-positive breast cancer. Anticancer Res 2016; 36: 2705-11.
  5. Kim YA, Lee HJ, Heo SH, et al. MxA expression is associated with tumor-infiltrating lymphocytes and is a prognostic factor in triplenegative breast cancer. Breast Cancer Res Treat 2016; 156: 597-606. https://doi.org/10.1007/s10549-016-3786-z
  6. Lee HJ, Park IA, Song IH, et al. Tertiary lymphoid structures: prognostic significance and relationship with tumour-infiltrating lymphocytes in triple-negative breast cancer. J Clin Pathol 2016; 69: 422-30. https://doi.org/10.1136/jclinpath-2015-203089
  7. Lee HJ, Song IH, Park IA, et al. Differential expression of major histocompatibility complex class I in subtypes of breast cancer is associated with estrogen receptor and interferon signaling. Oncotarget 2016; 7: 30119-32. https://doi.org/10.18632/oncotarget.8798
  8. Park IA, Heo SH, Song IH, et al. Endoplasmic reticulum stress induces secretion of high-mobility group proteins and is associated with tumor-infiltrating lymphocytes in triple-negative breast cancer. Oncotarget 2016; 7: 59957-64. https://doi.org/10.18632/oncotarget.11010
  9. Chen X, Iliopoulos D, Zhang Q, et al. XBP1 promotes triple-negative breast cancer by controlling the HIF1alpha pathway. Nature 2014; 508: 103-7. https://doi.org/10.1038/nature13119
  10. Han CC, Wan FS. New insights into the role of endoplasmic reticulum stress in breast cancer metastasis. J Breast Cancer 2018; 21: 354-62. https://doi.org/10.4048/jbc.2018.21.e51
  11. Oros Klein K, Oualkacha K, Lafond MH, Bhatnagar S, Tonin PN, Greenwood CM. Gene coexpression analyses differentiate networks associated with diverse cancers harboring TP53 missense or null mutations. Front Genet 2016; 7: 137.
  12. Kandioler-Eckersberger D, Ludwig C, Rudas M, et al. TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin Cancer Res 2000; 6: 50-6.
  13. Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 2009; 9: 701-13. https://doi.org/10.1038/nrc2693
  14. Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev 2012; 26: 1268-86. https://doi.org/10.1101/gad.190678.112
  15. Muller PA, Vousden KH. p53 mutations in cancer. Nat Cell Biol 2013; 15: 2-8. https://doi.org/10.1038/ncb2641
  16. Yue X, Zhao Y, Xu Y, Zheng M, Feng Z, Hu W. Mutant p53 in cancer: accumulation, gain-of-function, and therapy. J Mol Biol 2017; 429: 1595-606. https://doi.org/10.1016/j.jmb.2017.03.030
  17. Alsner J, Yilmaz M, Guldberg P, Hansen LL, Overgaard J. Heterogeneity in the clinical phenotype of TP53 mutations in breast cancer patients. Clin Cancer Res 2000; 6: 3923-31.
  18. Jin MS, Park IA, Kim JY, et al. New insight on the biological role of p53 protein as a tumor suppressor: re-evaluation of its clinical significance in triple-negative breast cancer. Tumour Biol 2016; 37: 11017-24. https://doi.org/10.1007/s13277-016-4990-5
  19. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490: 61-70. https://doi.org/10.1038/nature11412
  20. Duffy MJ, Synnott NC, McGowan PM, Crown J, O'Connor D, Gallagher WM. p53 as a target for the treatment of cancer. Cancer Treat Rev 2014; 40: 1153-60. https://doi.org/10.1016/j.ctrv.2014.10.004
  21. Duffy MJ, Synnott NC, Crown J. Mutant p53 as a target for cancer treatment. Eur J Cancer 2017; 83: 258-65. https://doi.org/10.1016/j.ejca.2017.06.023
  22. Kojima YA, Wang X, Sun H, Compton F, Covinsky M, Zhang S. Reproducible evaluation of tumor-infiltrating lymphocytes (TILs) using the recommendations of International TILs Working Group 2014. Ann Diagn Pathol 2018; 35: 77-9. https://doi.org/10.1016/j.anndiagpath.2018.05.007
  23. Park IA, Hwang SH, Song IH, et al. Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling. PLoS One 2017; 12: e0182786. https://doi.org/10.1371/journal.pone.0182786
  24. Adams S, Goldstein LJ, Sparano JA, Demaria S, Badve SS. Tumor infiltrating lymphocytes (TILs) improve prognosis in patients with triple negative breast cancer (TNBC). Oncoimmunology 2015; 4: e985930. https://doi.org/10.4161/2162402X.2014.985930
  25. Lee HJ, Kim A, Song IH, et al. Cytoplasmic expression of high mobility group B1 (HMGB1) is associated with tumor-infiltrating lymphocytes (TILs) in breast cancer. Pathol Int 2016; 66: 202-9. https://doi.org/10.1111/pin.12393
  26. Darb-Esfahani S, Denkert C, Stenzinger A, et al. Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy. Oncotarget 2016; 7: 67686-98. https://doi.org/10.18632/oncotarget.11891
  27. Maeda T, Nakanishi Y, Hirotani Y, et al. Immunohistochemical co-expression status of cytokeratin 5/6, androgen receptor, and p53 as prognostic factors of adjuvant chemotherapy for triple negative breast cancer. Med Mol Morphol 2016; 49: 11-21. https://doi.org/10.1007/s00795-015-0109-0
  28. Wu M, Wei W, Xiao X, et al. Expression of SIRT1 is associated with lymph node metastasis and poor prognosis in both operable triplenegative and non-triple-negative breast cancer. Med Oncol 2012; 29: 3240-9. https://doi.org/10.1007/s12032-012-0260-6
  29. Zhang J, Wang Y, Yin Q, Zhang W, Zhang T, Niu Y. An associated classification of triple negative breast cancer: the risk of relapse and the response to chemotherapy. Int J Clin Exp Pathol 2013; 6: 1380-91.
  30. Biganzoli E, Coradini D, Ambrogi F, et al. p53 status identifies two subgroups of triple-negative breast cancers with distinct biological features. Jpn J Clin Oncol 2011; 41: 172-9. https://doi.org/10.1093/jjco/hyq227
  31. Kashiwagi S, Yashiro M, Takashima T, et al. Advantages of adjuvant chemotherapy for patients with triple-negative breast cancer at Stage II: usefulness of prognostic markers E-cadherin and Ki67. Breast Cancer Res 2011; 13: R122. https://doi.org/10.1186/bcr3068
  32. Wang J, Zhang C, Chen K, et al. ERbeta1 inversely correlates with PTEN/PI3K/AKT pathway and predicts a favorable prognosis in triple-negative breast cancer. Breast Cancer Res Treat 2015; 152: 255-69. https://doi.org/10.1007/s10549-015-3467-3
  33. Lheureux S, Denoyelle C, Ohashi PS, De Bono JS, Mottaghy FM. Molecularly targeted therapies in cancer: a guide for the nuclear medicine physician. Eur J Nucl Med Mol Imaging 2017; 44(Suppl 1): 41-54.