Skip to main content

Advertisement

SpringerLink
Log in

Tissue microarray analysis of X-linked inhibitor of apoptosis (XIAP) expression in breast cancer patients

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

The goal of this study was to determine the diagnostic and prognostic potential of X-linked inhibitor of apoptosis (XIAP) expression in breast cancer. We analyzed a tissue microarray comprised of 100 breast cancer cases and 70 matched normal samples. Analysis of an online database, which included 2,977 patients, was also performed. There was a significant difference in cytoplasmic expression of XIAP (XIAP-C) between breast cancer tissue and matched normal (p < 0.001). Staining of XIAP-C was defined as negative (breast cancer 8.42 % vs. normal 30.91 %), slight (40.0 vs. 45.45 %), moderate (43.16 vs. 23.64 %), or high (8.42 vs. 0 %). High XIAP-C protein expression correlated with human epidermal growth factor receptor 2 (HER-2) status (p = 0.010) and with human p53 mutant-type (P53) status (p = 0.039). We found that XIAP expression did not correlate with disease-free survival (p = 0.706) and overall survival (p = 0.496) of breast cancer patients. An Internet-based system analysis confirmed our results. In the subgroup analysis, basal-like breast cancer patients with high XIAP levels in the tumor had a significantly increased risk of relapse; thus, the up-regulation of XIAP appeared to be predictive of poor relapse-free survival (p = 0.013). Kaplan–Meier curves also identified a significant correlation between distant metastasis-free survival and XIAP expression in patients with lymph-node-negative disease (p = 0.030). In summary, expression of XIAP-C was significantly higher in breast cancer compared to normal tissue. XIAP-C expression correlated with HER-2 status and may be considered a prognostic biomarker for basal-like breast cancer patients.

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
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Yuan Y, Liao Y-M, Hsueh C-T, Mirshahidi HR. Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. J Hematol Oncol. 2011;4:16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Firer MA, Gellerman G. Targeted drug delivery for cancer therapy: the other side of antibodies. J Hematol Oncol. 2012;5:70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Chaoquan H, Huang L, Gest C, Xi X, Janin A, Soria C, Li H, He L. Opposite regulation by PI3 K/Akt and MAPK/ERK pathways of tissue factor expression, cell-associated procoagulant activity and invasiveness in MDA-MB-231 cells. J Hematol Oncol. 2012;5:16.

    Article  Google Scholar 

  4. Chiang H-C, Nair SJ, Yeh I-T, Santillan AA, Hu Y, Elledge R, Li R. Association of radiotherapy with preferential depletion of luminal epithelial cells in a BRCA1 mutation carrier. Exp Hematol Oncol. 2012;1:31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Vaux DL, Silke J. Mammalian mitochondrial IAP binding proteins. Biochem Biophys Res Commun. 2003;3:499–504.

    Article  Google Scholar 

  6. Schimmer AD, Welsh K, Pinilla C, Wang Z, Krajewska M, Bonneau MJ, Pedersen IM, Kitada S, Scott FL, Bailly-Maitre B, Glinsky G, Scudiero D, Sausville E, Salvesen G, Nefzi A, Ostresh JM, Houghten RA, Reed JC. Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell. 2004;1:25–35.

    Article  Google Scholar 

  7. Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature. 1997;6639:300–4.

    Google Scholar 

  8. Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 1998;8:2215–23.

    Article  Google Scholar 

  9. Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS, Reed JC. Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J. 1999;18:5242–51.

    Article  CAS  PubMed  Google Scholar 

  10. Mohapatra S, Chu B, Zhao X, Pledger WJ. Accumulation of p53 and reductions in XIAP abundance promote the apoptosis of prostate cancer cells. Cancer Res. 2005;65:7717–23.

    CAS  PubMed  Google Scholar 

  11. Cummins MJ, Kohli M, Rago C, Kinzler KW, Vogelstein B, Bunz F. X-linked inhibitor of apoptosis protein (XIAP) is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human cancer cells. Cancer Res. 2004;64:3006–8.

    Article  CAS  PubMed  Google Scholar 

  12. Berezovskaya O, Schimmer AD, Glinskii AB, Pinilla C, Hoffman RM, Reed JC, Glinsky GV. Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. Cancer Res. 2005;65:2378–86.

    Article  CAS  PubMed  Google Scholar 

  13. Yang XH, Feng ZE, Yan M, Hanada S, Zuo H, Yang CZ, Han ZG, Guo W, Chen WT, Zhang P. XIAP is a predictor of cisplatin-based chemotherapy response and prognosis for patients with advanced head and neck cancer. PLoS One. 2012;3:e31601.

    Article  Google Scholar 

  14. Chen X, Wang T, Yang D, Wang J, Li X, He Z, Chen F, Che X, Song X. Expression of the IAP protein family acts cooperatively to predict prognosis in human bladder cancer patients. Oncol Lett. 2013;4:1278–84.

    Google Scholar 

  15. Shi YH, Ding WX, Zhou J, He JY, Xu Y, Gambotto AA, Rabinowich H, Fan J, Yin XM. Expression of X-linked inhibitor-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence. Hepatology. 2008;2:497–507.

    Article  Google Scholar 

  16. Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, Szallasi Z. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;3:725–31.

    Article  Google Scholar 

  17. Zhang Y, Wang Y, Gao W, Zhang R, Han X, Jia M, Guan W. Transfer of siRNA against XIAP induces apoptosis and reduces tumor cells growth potential in human breast cancer in vitro and in vivo. Breast Cancer Res Treat. 2006;3:267–77.

    Article  Google Scholar 

  18. Hu Y, Cherton-Horvat G, Dragowska V, Baird S, Korneluk RG, Durkin JP, Mayer LD, LaCasse EC. Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo. Clin Cancer Res. 2003;9:2826–36.

    CAS  PubMed  Google Scholar 

  19. Lima RT, Martins LM, Guimarães JE, Sambade C, Vasconcelos MH. Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Cancer Gene Ther. 2004;11:309–16.

    Article  CAS  PubMed  Google Scholar 

  20. Wang H, Huang M, Zhang DY, Zhang F. Global profiling of signaling networks: study of breast cancer stem cells and potential regulation. Oncologist. 2011;16:966–79.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang FC, Song SL, Ma Y, Tang L, Xu YC, Wang HX. Effect of fibroblasts on breast cancer cell mammosphere formation and the regulation of stem cell-related gene expression. Int J Mol Med. 2011;3:365–71.

    Google Scholar 

  22. Xu YC, Wang HX, Tang L, Ma Y, Zhang FC. A systematic review of vinorelbine for the treatment of breast cancer. Breast J. 2013;2:180–8.

    Article  Google Scholar 

  23. Wang HX, Zhang FC, Ye F, Ma Y, David YZ. The effect of coptis chinensis on the signaling network in the squamous carcinoma cells. Front Biosci. 2011;3:326–40.

    Article  Google Scholar 

  24. Zhang S, Ding F, Luo A, Chen A, Yu Z, Ren S, Liu Z, Zhang L. XIAP is highly expressed in esophageal cancer and its downregulation by RNAi sensitizes esophageal carcinoma cell lines to chemotherapeutics. Cancer Biol Ther. 2007;6:6973–80.

    Google Scholar 

  25. Bilim V, Yuuki K, Itoi T, Muto A, Kato T, Nagaoka A, Motoyama T, Tomita Y. Double inhibition of XIAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis. Br J Cancer. 2008;98:941–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Shi RX, Ong CN, Shen HM. Protein kinase C inhibition and x-linked inhibitor of apoptosis protein degradation contribute to the sensitization effect of luteolin on tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cancer cells. Cancer Res. 2005;65:7815–23.

    Article  CAS  PubMed  Google Scholar 

  27. Sun H, Lu J, Liu L, Yi H, Qiu S, Yang CY, Deschamps JR, Wang S. Nonpeptidic and potent small-molecule inhibitors of cIAP-1/2 and XIAP proteins. J Med Chem. 2010;17:6361–7.

    Article  Google Scholar 

  28. Amantana A, Lon don CA, Iversen PL, Devi GR. X-linked inhibitor of apoptosis protein inhibition induces apoptosis and enhances chemotherapy sensitivity in human prostate cancer cells. Mol Cancer Ther. 2004;3:699–707.

    CAS  PubMed  Google Scholar 

  29. Ming L, Tao S, Zhen-fei Y, Yan-qun NA. XIAP as a prognostic marker of early recurrence of nonmuscular invasive bladder cancer. Chin Med J. 2007;6:469–73.

    Google Scholar 

  30. Arnt CR, Chiorean MV, Heldebrant MP, Gores GJ, Kaufmann SH. Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ. J Biol Chem. 2002;46:44236–43.

    Article  Google Scholar 

  31. Mizutani Y, Nakanishi H, Li YN, Matsubara H, Yamamoto K, Sato N, Shiraishi T, Nakamura T, Mikami K, Okihara K. Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis. Int J Oncol. 2007;30:919–25.

    CAS  PubMed  Google Scholar 

  32. Che Y, Ye F, Xu R, Qing H, Wang X, Yin F, Cui M, Burstein D, Jiang B, Zhang DY. Co-expression of XIAP and cyclinD1 complex correlates with a poor prognosis in patients with hepatocellular carcinoma. Am J Pathol. 2012;5:1798–807.

    Article  Google Scholar 

  33. Zhang Y, Zhu J, Tang Y, Li F, Zhou H, Peng B, Zhou C, Fu R. X-linked inhibitor of apoptosis positive nuclear labeling: a new independent prognostic biomarker of breast invasive ductal carcinoma. Diagn Pathol. 2011;6:49.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Yang L, Cao Z, Yan H, Wood WC. Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. Cancer Res. 2003;20:6815–24.

    Google Scholar 

  35. Jaffer S, Orta L, Sunkara S, Sabo E, Burstein DE. Immunohistochemical detection of antiapoptotic protein X-linked inhibitor of apoptosis in mammary carcinoma. Hum Pathol. 2007;6:864–70.

    Article  Google Scholar 

  36. Vitté-Mony I, Korneluk RG, Diaz-Mitoma F. Role of XIAP protein, a human member of the inhibitor of apoptosis (IAP) protein family, in phytohemagglutinin-induced apoptosis of human T cell lines. Apoptosis. 1997;2:501–9.

    Article  PubMed  Google Scholar 

  37. Tenev T, Zachariou A, Wilson R, Ditzel M, Meier P. IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms. Nat Cell Biol. 2005;1:70–7.

    Article  Google Scholar 

  38. Xiang G, Wen X, Wang H, Chen K, Liu H. Expression of X-linked inhibitor of apoptosis protein in human colorectal cancer and its correlation with prognosis. J Surg Oncol. 2009;8:708–12.

    Google Scholar 

  39. Kim MA, Lee HE, Lee HS, Yang HK, Kim WH. Expression of apoptosis-related proteins and its clinical implication in surgically resected gastric carcinoma. Virchows Arch. 2011;5:503–10.

    Article  Google Scholar 

  40. Aird KM, Ding X, Baras A, Wei J, Morse MA, Clay T, Lyerly HK, Devi GR. Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression. Mol Cancer Ther. 2008;1:38–47.

    Article  Google Scholar 

Download references

Acknowledgments

We thank Dr Stephen Clarke and Scientist Lucy in the Kolling Institute of RNS Hospital of Austria for technical assistance and paper revision. Written consent for publication is obtained from the patients or their relatives. This study was supported by the National Natural Science Funds (Project Number: 81102015 and 81301858), the National Program on Key Basic Research Project (973 Program) (Project Number: 2013CB967201), the Special Funds for Technological Innovation of Shanghai Jiaotong University (Project Number: YG2012MS46) and Shanghai Municipal Commission of Health and Family Planning.

Conflict of interests

This paper has never been published and is not under simultaneous review by another journal. All authors have read and approved to submit it to your journal. There is no conflict of interest of any authors in relation to the submission.

Author information

Authors and Affiliations

  1. Department of Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Ying-Chun Xu, Lei Tang, Yue Ma, Xiao-Lin Lin & Hong-Xia Wang

  2. Department of Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Jia-Qi Dai & Zhi-Qiang Yin

  3. Department of Pathology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Qiang Liu

Authors
  1. Ying-Chun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jia-Qi Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhi-Qiang Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yue Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao-Lin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hong-Xia Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhi-Qiang Yin or Hong-Xia Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, YC., Liu, Q., Dai, JQ. et al. Tissue microarray analysis of X-linked inhibitor of apoptosis (XIAP) expression in breast cancer patients. Med Oncol 31, 764 (2014). https://doi.org/10.1007/s12032-013-0764-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-013-0764-8

Keywords

Search

Navigation