Tumor Biology

, Volume 37, Issue 2, pp 2603–2611 | Cite as

Breast cancer cells respond differently to docetaxel depending on their phenotype and on survivin upregulation

  • Francesca De Iuliis
  • Gerardo Salerno
  • Anna Giuffrida
  • Bernardina Milana
  • Ludovica Taglieri
  • Giovanna Rubinacci
  • Sabrina Giantulli
  • Federica Terella
  • Ida Silvestri
  • Susanna Scarpa
Original Article


Breast cancer is characterized by molecular heterogeneity, and four major breast cancer subtypes have been identified, each characterized by significant differences in survival, prognosis, and response to therapy. We have studied the effects of docetaxel treatment on apoptosis and survivin expression in four breast cancer cell lines: MCF7 (luminal A: estrogen receptor-positive and progesterone receptor-positive, ErbB2-negative), BT474 (luminal B: estrogen receptor/progesterone receptor/ErbB2-positive), SKBR3 (HER2-like: estrogen receptor/progesterone receptor-negative, ErbB2-positive), and MDA-MB231 (basal-like: estrogen receptor/progesterone receptor/ErbB2-negative). We demonstrated that docetaxel-induced apoptosis and survivin upregulation (MCF7 p = 0.002, BT474 p = 0.001, SKBR3 p = 0.001) in luminal A/B and HER2-like cells, while it induced mainly necrosis and a lower rate of survivin upregulation (MDA-MB231 p = 0.035) in basal-like cells. Wortmannin, a p-Akt inhibitor, was able to revert surviving upregulation and, at the same time, induced an increase of docetaxel-dependent apoptosis, suggesting that reduced levels of survivin can sensitize tumor cells to apoptosis. These data show that the analyzed breast cancer cell lines respond differently to docetaxel, depending on their receptor expression profile and molecular phenotype. Yet, these data confirm that one of the pathways involved in taxane-related chemoresistance is the upregulation of survivin. Further studies on the molecular mechanisms of chemoresistance and on the different modalities of apoptosis induced by chemotherapeutic agents are requested to better understand how cancer cells evade cell death, in order to design new kind of anticancer agents and survivin could represent a future target for this kind of research.


Survivin Breast cancer Docetaxel Apoptosis Chemoresistance Wortmannin 


Conflicts of interest



  1. 1.
    Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF, et al. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors. Nature. 2012;490(7418):61–70.CrossRefGoogle Scholar
  2. 2.
    Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379(9814):432–44.CrossRefPubMedGoogle Scholar
  3. 3.
    Jones SE, Savin MA, Holmes FA, O’Shaughnessy JA, Blum JL, Vukelja S, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006;24(34):5381–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Dalton WS. Mechanisms of drug resistance in breast cancer. Semin Oncol. 1990;17(7):37–9.PubMedGoogle Scholar
  5. 5.
    Hunter AM, LaCasse EC, Korneluk RG. The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis. 2007;12(9):1543–68.CrossRefPubMedGoogle Scholar
  6. 6.
    Foster FM, Owens TW, Tanianis-Hughes J, Clarke RB, Brennan K, Bundred NJ, et al. Targeting inhibitor of apoptosis proteins in combination with ErbB antagonists in breast cancer. Breast Cancer Res. 2009;11(3):R41.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Byun SS, Yeo WG, Lee SE, Lee E. Expression of survivin in renal cell carcinomas: association with pathologic features and clinical out come. Urology. 2007;69(1):34–7.CrossRefPubMedGoogle Scholar
  8. 8.
    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(4):639–45.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Vucic D, Fairbrother WJ. The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clin Cancer Res. 2007;13(20):5995–6000.CrossRefPubMedGoogle Scholar
  10. 10.
    LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Baird S, Korneluk RG. IAP-targeted therapies for cancer. Oncogene. 2008;27(48):6252–75.CrossRefPubMedGoogle Scholar
  11. 11.
    Murray S, Briasoulis E, Linardou H, Bafaloukos D, Papadimitriou C. Taxane resistance in breast cancer: mechanisms, predictive biomarkers and circumvention strategies. Cancer Treat Rev. 2012;38(7):890–903.CrossRefPubMedGoogle Scholar
  12. 12.
    Vichaj V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006;1(3):1112–6.CrossRefGoogle Scholar
  13. 13.
    Papapetropoulos A, Fulton D, Mahboui K, Kalb RG, O’Connor D, Li F, et al. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem. 2000;275(13):9102–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Altieri DC. The case for survivin as a regulator of microtubule dynamics and cell-death decisions. Curr Opin Cell Biol. 2006;18(6):609–15.CrossRefPubMedGoogle Scholar
  15. 15.
    Lv YG, Yu F, Yao Q, Chen JH, Wang L. The role of survivin in diagnosis, prognosis and treatment of breast cancer. J Thorac Dis. 2010;2(2):100–10.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Virrey JJ, Guan S, Li W, Schontal AH, Chen TC, Hofman FM. Increased surviving expression confers chemoresistance to tumor associated endothelial cells. Am J Pathol. 2008;173(2):575–85.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Siddiqa A, Long LM, Li L, Marciniak RA, Kazhdan I. Expression of HER-2 in MCF-7 breast cancer cells modulates anti-apoptotic protein sSurvivin and Bcl-2 via the extracellular signal-related kinase (ERK) and phosphoinositide-3 kinase (PI3K) signaling pathways. BMC Cancer. 2008;8:129.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ceballos-Cancino G, Espinosa M, Maldonado V, Melendez-Zajgla J. Regulation of mitochondrial Smac/DIABLO-selective release by survivin. Oncogene. 2007;26(54):7569–75.CrossRefPubMedGoogle Scholar
  19. 19.
    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 receptor2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/AKT signaling pathway in breast cancer cells. Cancer Res. 2005;65(23):11018–25.CrossRefPubMedGoogle Scholar
  20. 20.
    Xia W, Bisi J, Strum J, Liu L, Carrick K, Graham KM, et al. Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res. 2006;66(3):1640–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Jiang H, Yu J, Guo H, Song H, Chen S. Upregulation of survivin by leptin/STAT3 signaling in MCF-7 cells. Biochem Biophys Res Commun. 2008;368(1):1–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Ju JH, Yang W, Oh S, Nam K, Lee KM, Noh DY, et al. HER2 stabilizes surviving while concomitantly down-regulating survivin gene transcription by suppressing Notch cleavage. Biochem J. 2013;451(1):123–34.CrossRefPubMedGoogle Scholar
  23. 23.
    Wall NR, O’Connor DS, Plescia J, Pommier Y, Altieri DC. Suppression of surviving phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. Cancer Res. 2003;63(1):230–5.PubMedGoogle Scholar
  24. 24.
    Lu J, Tan M, Huang WC, Li P, Guo H, Tseng LM, et al. Mitotic deregulation by survivin in ErbB2-overexpressing breast cancer cells contributes to Taxol resistance. Clin Cancer Res. 2009;15(4):1326–34.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lips EH, Mulder L, De Ronde JJ, Mandjes IA, Vincent A, Vrancken Peeters MT, et al. Neoadjuvant chemotherapy in ER+ HER2- breast cancer: response prediction based on immunohistochemical and molecular characteristics. Breast Cancer Res Treat. 2012;131(3):827–36.CrossRefPubMedGoogle Scholar
  26. 26.
    Sui M, Huang Y, Park BH, Davidson NE, Fan W. Estrogen receptor alpha mediates breast cancer cell resistance to paclitaxel through inhibition of apoptotic cell death. Cancer Res. 2007;67(11):5337–44.CrossRefPubMedGoogle Scholar
  27. 27.
    Hatzis C, Pusztai L, Valero V, Booser DJ, Esserman L, Lluch A, et al. A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. JAMA. 2011;305(18):1873–81.CrossRefPubMedGoogle Scholar
  28. 28.
    Yu D, Liu B, Tan M, Li J, Wang SS, Hung MC. Overexpression of c-erbB-2/neu in breast cancer cells confers increased resistance to Taxol via mdr-1-independent mechanisms. Oncogene. 1996;13(6):1359–65.PubMedGoogle Scholar
  29. 29.
    Ghanbari P, Mohseni M, Tabasinezhad M, Yousefi B, Saei AA, Sharifi S, et al. Inhibition of survivin restores the sensitivity of breast cancer cells to docetaxel and vinblastine. Appl Biochem Biotechnol. 2014;174(2):667–81.CrossRefPubMedGoogle Scholar
  30. 30.
    Cheung CH, Huang CC, Tsai FY, Lee JY, Cheng SM, Chang YC, et al. Survivin-biology and potential as a therapeutic target in oncology. Onco Targets Ther. 2013;6:1453–62.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lv YG, Yu F, Yao Q, Chen JH, Wang L. The role of survivin in diagnosis, prognosis and treatment of breast cancer. J Thorac Dis. 2010;2(2):100–10.PubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Francesca De Iuliis
    • 1
  • Gerardo Salerno
    • 1
  • Anna Giuffrida
    • 1
  • Bernardina Milana
    • 2
  • Ludovica Taglieri
    • 1
  • Giovanna Rubinacci
    • 2
  • Sabrina Giantulli
    • 2
  • Federica Terella
    • 2
  • Ida Silvestri
    • 2
  • Susanna Scarpa
    • 1
  1. 1.Experimental Medicine DepartmentSapienza University of RomeRomeItaly
  2. 2.Molecular Medicine DepartmentSapienza University of RomeRomeItaly

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