pISSN 1738-6756   eISSN 2092-9900
Open Access, Peer-reviewed
    J Breast Cancer. 2009 Dec;12(4):285-294. Korean.
    Published online Dec 31, 2009.
    https://doi.org/10.4048/jbc.2009.12.4.285
    Copyright © 2009 Korean Breast Cancer Society
    Original Article

    The Prognostic Significance of Survivin Expression in Breast Cancer

    Jae-Won Oh,1 Woo-Ick Yang,2 Mi Jeong Lee,3 Seho Park,1 Byeong-Woo Park,1,3 and Kyong-Sik Lee4
      • 1Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.
      • 2Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
      • 3Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea.
      • 4Department of Surgery, Pochon CHA University College of Medicine, Seongnam, Korea.
    • Corresponding author (Email: bwpark@yumc.yonsei.ac.kr )
    Received April 03, 2009; Accepted June 02, 2009.

    Abstract

    Purpose

    Survivin is a member of the inhibitors of apoptosis family. It has recently comes into the limelight as a promising tumor marker, but many previous reports have shown controversial results regarding the significance and prognostic value of a survivin expression. In this study we determined the correlation between the survivin expression and the conventional prognostic markers and we also investigated the outcomes according to the localization of the survivin expression.

    Methods

    Tissue microarray (TMA) blocks were made with formalin-fixed paraffin-embedded tissues from 185 breast cancer patients and the immunohistochemical staining was done using an anti-survivin antibody. Among these, 157 patients were available for a survivin expression. The conventional clinicopathologic features and overall survival were correlated with the localization of the survivin expression.

    Results

    Survivin was expressed in 101 breast cancers (64.3%). A higher cytoplasmic survivin expression were noted in the older group (p=0.003), in the node-negative cancers (p=0.012), in the earlier tumor stages (p=0.012) and in the cancers that had not been treated with adjuvant chemotherapy (p=0.014). On the contrary, a higher nuclear survivin expression was inversely correlated with an estrogen expression (p=0.006) and a progesterone receptor (p=0.043) expression. In terms of survival, a cytoplasmic expression was associated with improved overall survival (p=0.01) but a nuclear survivin expression was correlated with unfavorable overall survival (p=0.002). A high cytoplasmic to nuclear ratio of survivin was associated with improved overall survival (p=0.001) conversely, increased nuclear to cytoplasmic survivin ratio was correlated with unfavorable overall survival (p<0.0001). Multivariate analysis revealed that nuclear survivin expression (p=0.001) and high nuclear to cytoplasmic survivin ratio (p=0.012) were independent predictor of overall survival.

    Conclusion

    Survivin is frequently expressed in primary breast cancer. A cytoplasmic survivin expression is a good prognostic predictor for patients with axillary node negative early breast cancers and a nuclear survivin expression is a worse independent predictor of overall survival for patients with axillary node positive breast cancers.

    Keywords
    Breast neoplasms; Prognostic factor; Survivin

    Figures

    Figure 1
    Immunohistochemical staining results for survivin (DAB with hematoxylin counterstaining). (A) Nuclear staining of survivin (×200), (B) Cytoplasmic and nuclear staining of survivin (×200), (C) Cytoplasmic staining of survivin (×200) in invasive ductal carcinoma.

    Figure 2
    Kaplan-Meier survival estimates for positive and negative cases of breast cancer regarding (A) cytoplasmic survivin expression and (B) nuclear survivin expression.

    Figure 3
    Kaplan-Meier survival estimates for using a ratio of 2 as a cutoff. (A) cytoplasmic to nuclear survivin expression ratio and (B) nuclear to cytoplasmic survivin expression ratio.

    Figure 4
    Kaplan-Meier survival curve according to lymph node negative group (A) and lymph node positive group (B) categorized by cytoplasmic survivin expression.

    Figure 5
    Kaplan-Meier survival curve according to lymph node negative group (A) and lymph node positive group (B) categorized by nuclear survivin expression.

    Figure 6
    Kaplan-Meier survival curve according to TNM stage categorized by cytoplasmic survivin expression.

    Figure 7
    Kaplan-Meier survival curve according to TNM stage categorized by nuclear survivin expression.

    Tables

    Table 1
    Patients characteristics

    Table 2
    Localization of survivin expression by immunochemical methods

    Table 3
    Association between survivin expression and tumor characteristics

    Table 4
    Prognostic significance of clinicopathologic variables

    Table 5
    Multivariate Cox proportional hazard model for overall survival

    References

      1. Jiang X, Wilford C, Duensing S, Munger K, Jones G, Jones D. Participation of survivin in mitotic and apoptotic activities of normal and tumor-derived cells. J Cell Biochem 2001;83:342–354.
      1. Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998;396:580–584.
      1. LaCasse EC, Baird S, Korneluk RG, MacKenzie AE. The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 1998;17:3247–3259.
      1. Altieri DC. Validating survivin as a cancer therapeutic target. Nat Rev Cancer 2003;3:46–54.
      1. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997;3:917–921.
      1. Kawasaki H, Altieri D, Lu CD, Toyoda M, Tenjo T, Tanigawa N. Inhibition of apoptosis by survivin predict shorter survival rates in colorectal cancer. Cancer Res 1998;58:5071–5074.
      1. Ikeguchi M, Kaibara N. Survivin messenger RNA expression is a good prognostic biomarker for oesophageal carcinoma. Br J Cancer 2002;87:883–887.
      1. Wall NR, O'Connor DS, Plescia J, Pommier Y, Altieri DC. Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. Cancer Res 2003;63:230–235.
      1. Zaffaroni N, Pennati M, Colella G, Perego P, Supino R, Gatti L, et al. Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer. Cell Mol Life Sci 2002;59:1406–1412.
      1. Zhang W, Chen X, Qiu F. An antisense plasmid targeting survivin expression induces apoptosis and sensitizes hepatocarcinoma cells to chemotherapy. J Huazhong Univ Sci Technolog Med Sci 2003;23:387–391.
      1. Cao C, Mu Y, Hallahan DE, Bo Lu. XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer. Oncogene 2004;23:7047–7052.
      1. Kayaselcuk F, Nursal TZ, Polat A, Noyan T, Yildirim S, Tarim A, et al. Expression of survivin, bcl-2, P53 and bax in breast carcinoma and ductal intraepithelial neoplasia (DIN 1a). J Exp Clin Cancer Res 2004;23:105–112.
      1. Kennedy SM, O'Driscoll L, Purcell R, Fitz-Simons N, McDermott EW, Hill AD, et al. Prognostic importance of survivin in breast cancer. Br J Cancer 2003;88:1077–1083.
      1. Ryan BM, Konecny GE, Kahlert S, Wang HJ, Untch M, Meng G, et al. Survivin expression in breast cancer predicts clinical outcome and is associated with HER2, VEGF, urokinase plasminogen activator and PAI-1. Ann Oncol 2006;17:597–604.
      1. Altieri DC. Validating survivin as a cancer therapeutic target. Nat Rev Cancer 2003;3:46–54.
      1. Bao R, Connolly DC, Murphy M, Green J, Weinstein JK, Pisarcik DA, et al. Activation of cancer-specific gene expression by the survivin promoter. J Natl Cancer Inst 2002;94:522–528.
      1. Span PN, Sweep FC, Weigerinck ET, Tjan-Heijnen VC, Manders P, Beex LV, et al. Survivin is an independent prognostic marker for risk stratification of breast cancer patients. Clin Chem 2004;50:1986–1993.
      1. Asanuma H, Torigoe T, Kamiguchi K, Hirohashi Y, Ohmura T, Hirata K, et al. Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/AKT signalling pathway in breast cancer cells. Cancer Res 2005;65:11018–11025.
      1. Tsuji N, Furuse K, Asanuma K, Furuya M, Kondoh K, Kamagata C, et al. Mutations of the p53 gene and loss of heterozygosity at chromosome 17p13.1 are associated with increased surviving expression in breast cancer. Breast Cancer Res Treat 2004;87:23–31.
      1. Tanaka K, Iwamoto S, Gon G, Nohara T, Iwamoto M, Tanigawa N. Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Cancer Res 2000;6:127–134.
      1. Chu JS, Shew JY, Huang CS. Immunohistochemical analysis of survivin expression in primary breast cancers. J Formos Med Assoc 2004;103:925–931.
      1. O'Driscoll L, Linehan R, M Kennedy S, Cronin D, Purcell R, Glynn S, et al. Lack of prognostic significance of survivin, survivin-deltaEx3, survivin-2B, galectin-3, bag-1, bax-alpha and MRP-1 mRNAs in breast cancer. Cancer Lett 2003;201:225–236.
      1. Hinnis AR, Luckett JC, Walker RA. Survivin is an independent predictor of short-term survival in poor prognostic breast cancer patients. Br J Cancer 2007;96:639–645.
      1. Okada E, Murai Y, Matsui K, Isizawa S, Cheng C, Masuda M, et al. Survivin expression in tumor cell nuclei is predictive of a favorable prognosis in gastric cancer patients. Cancer Lett 2001;163:109–116.
      1. Grabowski P, Kühnel T, Mühr-Wilkenshoff F, Heine B, Stein H, Höpfner M, et al. Prognostic value of nuclear survivin expression in oesophageal squamous cell carcinoma. Br J Cancer 2003;88:115–119.
      1. Lu B, Gonzalez A, Massion PP, Shyr Y, Shaktour B, Carbone DP, et al. Nuclear survivin as a biomarker for non-small-cell lung cancer. Br J Cancer 2004;91:537–540.
      1. Li F, Yang J, Ramnath N, Javle MM, Tan D. Nuclear or cytoplasmic expression of survivin: what is the significance? Int J Cancer 2005;114:509–512.
      1. Brennan DJ, Rexhepaj E, O'Brien SL, McSherry E, O'Connor DP, Fagan A, et al. Altered cytoplasmic-to-nuclear ratio of survivin is a prognostic indicator in breast cancer. Clin Cancer Res 2008;14:2681–2689.
      1. Fortugno P, Wall NR, Giodini A, O'Connor DS, Plescia J, Padgett KM, et al. Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function. J Cell Sci 2001;115:575–585.
      1. Mahotka C, Wenzel M, Springer E, Gabbert HE, Gerharz CD. Survivin-deltaEx3 and survivin-2B: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties. Cancer Res 1999;59:6097–6102.
      1. Badran A, Yoshida A, Ishikawa K, Goi T, Yamaguchi A, Ueda T, et al. Identification of a novel splice variant of the human anti-apoptosis gene survivin. Biochem Biophys Res Commun 2004;314:902–907.
    Cited by
    Crossref 2
    Google Scholar 
    Scopus 5
    Web of Science 5
    MeSH Terms
    Apoptosis
    Breast
    Breast Neoplasms
    Chemotherapy, Adjuvant
    Cytoplasm
    Estrogens
    Humans
    Multivariate Analysis
    Receptors, Progesterone
    Metrics
    Share
    Figures
    slide
    slide
    slide
    slide
    slide
    slide
    slide

    1 / 7

    Tables
    slide
    slide
    slide
    slide
    slide

    1 / 5

    PERMALINK