Journal of Cancer Research and Clinical Oncology

, Volume 138, Issue 2, pp 327–332 | Cite as

Shorter disease-specific survival of ER-positive breast cancer patients with high cytoplasmic Src kinase expression after tamoxifen treatment

  • B. Elsberger
  • D. M. Paravasthu
  • S. M. Tovey
  • J. Edwards
Original Paper

Abstract

Background

Src kinase, a non-receptor tyrosine kinase, is overexpressed and highly activated in a number of human cancers and appears to show a significant relationship with breast cancer progression. Recent in vitro studies have suggested that Src kinase may be involved in tamoxifen resistance.

Methods

Immunohistochemistry was performed on 392 resected breast cancers using an antibody to c-Src. Expression was assessed using the weighted histoscore method.

Results

Forty-five percentage of breast tumours exhibited nuclear, 46% cytoplasmic and 7% membrane expression. Lymph node positivity correlated with cytoplasmic c-Src tumour expression levels (P < 0.001). Nuclear c-Src correlated negatively with cytoplasmic and membrane c-Src expression (P < 0.001, P = 0.005). High expression levels of cytoplasmic c-Src was associated with worse disease-specific survival (P = 0.026) after completing 5 years of tamoxifen therapy. However, high expression of c-Src at any cellular location did not show any association with de novo relapse on tamoxifen (c-Src nuc P = 0.906, c-Src cyto P = 0.735 and c-Src memb P = 0.791).

Conclusions

No translational evidence was found in this study to support a role for Src kinase in developing de novo tamoxifen resistance. However, based on our findings on late clinical outcome, patients with high cytoplasmic c-Src may be selected for continuing endocrine therapy to prevent worsening prognosis.

Keywords

Src kinase ER-positive breast cancer Disease-specific survival Immunohistochemistry Tamoxifen 

References

  1. Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ (2000) Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Res 2:203–210PubMedCrossRefGoogle Scholar
  2. Bjorge JD, Jakymiw A, Fujita DJ (2000) Selected glimpses into the activation and function of Src kinase. Oncogene 19:5620–5635PubMedCrossRefGoogle Scholar
  3. Campbell EJ, McDuff E, Tatarov O, Tovey S, Brunton V, Cooke TG, Edwards J (2008) Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer. Br J Cancer 99:1769–1774PubMedCrossRefGoogle Scholar
  4. Elsberger B, Tan BA, Mitchell TJ, Brown SB, Mallon EA, Tovey SM, Cooke TG, Brunton VG, Edwards J (2009) Is expression or activation of Src kinase associated with cancer-specific survival in ER-, PR- and HER2-negative breast cancer patients? Am J Pathol 175:1389–1397PubMedCrossRefGoogle Scholar
  5. Frame MC (2002) Src in cancer: deregulation and consequences for cell behaviour. Biochim Biophys Acta 1602:114–130PubMedGoogle Scholar
  6. Hiscox S, Morgan L, Green TP, Barrow D, Gee J, Nicholson RI (2006) Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells. Breast Cancer Res Treat 97:263–274PubMedCrossRefGoogle Scholar
  7. Keam SJ (2008) Dasatinib: in chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. BioDrugs 22:59–69PubMedCrossRefGoogle Scholar
  8. Kim H, Laing M, Muller W (2005) c-Src-null mice exhibit defects in normal mammary gland development and ERalpha signaling. Oncogene 24:5629–5636PubMedCrossRefGoogle Scholar
  9. Kirkegaard T, Edwards J, Tovey S, McGlynn LM, Krishna SN, Mukherjee R, Tam L, Munro AF, Dunne B, Bartlett JM (2006) Observer variation in immunohistochemical analysis of protein expression, time for a change? Histopathology 48:787–794PubMedCrossRefGoogle Scholar
  10. Mamidipudi V, Dhillon NK, Parman T, Miller LD, Lee KC, Cartwright CA (2007) RACK1 inhibits colonic cell growth by regulating Src activity at cell cycle checkpoints. Oncogene 26:2914–2924PubMedCrossRefGoogle Scholar
  11. Morgan L, Gee J, Pumford S, Farrow L, Finlay P, Robertson J, Ellis I, Kawakatsu H, Nicholson R, Hiscox S (2009) Elevated Src kinase activity attenuates Tamoxifen response in vitro and is associated with poor prognosis clinically. Cancer Biol Ther 8:1550–1558PubMedCrossRefGoogle Scholar
  12. Nigg EA, Sefton BM, Hunter T, Walter G, Singer SJ (1982) Immunofluorescent localization of the transforming protein of Rous sarcoma virus with antibodies against a synthetic src peptide. Proc Natl Acad Sci USA 79:5322–5326PubMedCrossRefGoogle Scholar
  13. Planas-Silva MD, Bruggeman RD, Grenko RT, Stanley SJ (2006) Role of c-Src and focal adhesion kinase in progression and metastasis of estrogen receptor-positive breast cancer. Biochem Biophys Res Commun 341:73–81PubMedCrossRefGoogle Scholar
  14. Sandilands E, Brunton VG, Frame MC (2007) The membrane targeting and spatial activation of Src, Yes and Fyn is influenced by palmitoylation and distinct RhoB/RhoD endosome requirements. J Cell Sci 120:2555–2564PubMedCrossRefGoogle Scholar
  15. Schiff R, Massarweh SA, Shou J, Bharwani L, Mohsin SK, Osborne CK (2004) Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin Cancer Res 10:331S–336SPubMedCrossRefGoogle Scholar
  16. Tatarov O, Mitchell TJ, Seywright M, Leung HY, Brunton VG, Edwards J (2009) SRC family kinase activity is up-regulated in hormone-refractory prostate cancer. Clin Cancer Res 15:3540–3549PubMedCrossRefGoogle Scholar
  17. Timpson P, Jones GE, Frame MC, Brunton VG (2001) Coordination of cell polarization and migration by the Rho family GTPases requires Src tyrosine kinase activity. Curr Biol 11:1836–1846PubMedCrossRefGoogle Scholar
  18. Verbeek BS, Vroom TM, Adriaansen-Slot SS, Ottenhoff-Kalff AE, Geertzema JG, Hennipman A, Rijksen G (1996) c-Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis. J Pathol 180:383–388PubMedCrossRefGoogle Scholar
  19. Yeatman TJ (2004) A renaissance for SRC. Nat Rev Cancer 4:470–480PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • B. Elsberger
    • 1
  • D. M. Paravasthu
    • 1
  • S. M. Tovey
    • 2
  • J. Edwards
    • 1
  1. 1.Institute of Cancer, College of Medical, Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
  2. 2.Department of SurgeryCrosshouse HospitalKilmarnockUK

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