Skip to main content

Advertisement

SpringerLink
Log in

LMTK3 expression in breast cancer: association with tumor phenotype and clinical outcome

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Interactions between kinases and the estrogen receptor α (ERα) are thought to be a critical signaling pathway in the majority of human breast cancers. We have recently identified a previously uncharacterized molecule, lemur tyrosine kinase-3 (LMTK3) as a prognostic and predictive oncogenic ERα regulator with a central role in endocrine resistance. Unusually this protein has undergone Darwinian positive selection between Chimpanzees and humans suggesting it may contribute to human susceptibility to ERα-positive tumors. Using over 600 European primary breast cancer cases, we wished to establish tumor characteristics associated with both cytoplasmic and nuclear LMTK3 expression, and then externally validate our observed European clinical outcomes with samples from Asian individuals receiving chemotherapy. Both nuclear and cytoplasmic expression correlated with tumor grade (P < 0.001) and in the Asian cohort, independent blinded analyses demonstrated that high basal LMTK3 expression was associated with advanced stage of primary breast cancers as well as decreased overall (P = 0.03) and disease-free survival (P = 0.006). In summary, higher LMTK3 expression is associated with more aggressive cancers. These data support our previous findings and suggest LMTK3 expression may be a reliable new biomarker in breast cancer.

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

Similar content being viewed by others

References

  1. Stebbing J, Crane J, Gaya A (2006) Breast cancer (metastatic). Clin Evid 15:2331–2359

    PubMed  Google Scholar 

  2. Stebbing J, Delaney G, Thompson A (2007) Breast cancer (non-metastatic). Clin Evid (Online) 6718–6753

  3. Hammond ME, Hayes DF, Dowsett M et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2784–2795

    Article  PubMed  Google Scholar 

  4. Kato S, Endoh H, Masuhiro Y et al (1995) Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270:1491–1494

    Article  PubMed  CAS  Google Scholar 

  5. Ali S, Coombes RC (2002) Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2:101–112

    Article  PubMed  Google Scholar 

  6. Amanchy R, Kalume DE, Iwahori A, Zhong J, Pandey A (2005) Phosphoproteome analysis of HeLa cells using stable isotope labeling with amino acids in cell culture (SILAC). J Proteome Res 4:1661–1671

    Article  PubMed  CAS  Google Scholar 

  7. Atsriku C, Britton DJ, Held JM et al (2009) Systematic mapping of posttranslational modifications in human estrogen receptor-alpha with emphasis on novel phosphorylation sites. Mol Cell Proteomics 8:467–480

    Article  PubMed  CAS  Google Scholar 

  8. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 276:9817–9824

    Article  PubMed  CAS  Google Scholar 

  9. Britton DJ, Scott GK, Schilling B et al (2008) A novel serine phosphorylation site detected in the N-terminal domain of estrogen receptor isolated from human breast cancer cells. J Am Soc Mass Spectrom 19:729–740

    Article  PubMed  CAS  Google Scholar 

  10. Wu RC, Qin J, Yi P et al (2004) Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic responses to multiple cellular signaling pathways. Mol Cell 15:937–949

    Article  PubMed  CAS  Google Scholar 

  11. Jiang J, Sarwar N, Peston D et al (2007) Phosphorylation of estrogen receptor-alpha at Ser167 is indicative of longer disease-free and overall survival in breast cancer patients. Clin Cancer Res 13:5769–5776

    Article  PubMed  CAS  Google Scholar 

  12. Giamas G, Castellano L, Feng Q et al (2009) CK1delta modulates the transcriptional activity of ERalpha via AIB1 in an estrogen-dependent manner and regulates ERalpha-AIB1 interactions. Nucleic Acids Res 37:3110–3123

    Article  PubMed  CAS  Google Scholar 

  13. Chen D, Washbrook E, Sarwar N et al (2002) Phosphorylation of human estrogen receptor alpha at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera. Oncogene 21:4921–4931

    Article  PubMed  CAS  Google Scholar 

  14. Giamas G, Filipovic A, Jacob J et al (2011) Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer. Nat Med (Advanced online publication) 17(6):715–719

    CAS  Google Scholar 

  15. Bowen RL, Stebbing J, Jones LJ (2006) A review of the ethnic differences in breast cancer. Pharmacogenomics 7:935–942

    Article  PubMed  CAS  Google Scholar 

  16. Dunn BK, Agurs-Collins T, Browne D, Lubet R, Johnson KA (2010) Health disparities in breast cancer: biology meets socioeconomic status. Breast Cancer Res Treat 121:281–292

    Article  PubMed  Google Scholar 

  17. Chuah BY, Putti T, Salto-Tellez M et al (2011) Serial changes in the expression of breast cancer-related proteins in response to neoadjuvant chemotherapy. Ann Oncol. doi:10.1093/annonc/mdq755

  18. Walker RA, Bartlett JM, Dowsett M et al (2008) HER2 testing in the UK: further update to recommendations. J Clin Pathol 61:818–824

    Article  PubMed  CAS  Google Scholar 

  19. Bartlett JM, Ellis IO, Dowsett M et al (2007) Human epidermal growth factor receptor 2 status correlates with lymph node involvement in patients with estrogen receptor (ER) negative, but with grade in those with ER-positive early-stage breast cancer suitable for cytotoxic chemotherapy. J Clin Oncol 25:4423–4430

    Article  PubMed  Google Scholar 

  20. Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410

    Article  PubMed  CAS  Google Scholar 

  21. Ellis IO, Galea M, Broughton N, Locker A, Blamey RW, Elston CW (1992) Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up. Histopathology 20:479–489

    Article  PubMed  CAS  Google Scholar 

  22. Parker C, Rampaul RS, Pinder SE et al (2001) E-cadherin as a prognostic indicator in primary breast cancer. Br J Cancer 85:1958–1963

    Article  PubMed  CAS  Google Scholar 

  23. Madjd Z, Parsons T, Watson NF, Spendlove I, Ellis I, Durrant LG (2005) High expression of Lewis y/b antigens is associated with decreased survival in lymph node negative breast carcinomas. Breast Cancer Res 7:R780–R787

    Article  PubMed  CAS  Google Scholar 

  24. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229–235

    Article  PubMed  Google Scholar 

  25. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) Reporting recommendations for tumor marker prognostic studies (remark). Exp Oncol 28:99–105

    PubMed  CAS  Google Scholar 

  26. Giamas G, Stebbing J, Vorgias CE, Knippschild U (2007) Protein kinases as targets for cancer treatment. Pharmacogenomics 8:1005–1016

    Article  PubMed  CAS  Google Scholar 

  27. Giamas G, Man YL, Hirner H et al (2010) Kinases as targets in the treatment of solid tumors. Cell Signal 22:984–1002

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 ONN, UK

    Justin Stebbing, Aleksandra Filipovic, Tanya Rapoz D’Silva, R. Charles Coombes & Georgios Giamas

  2. Department of Cellular Pathology, Queen’s Medical Centre, Nottingham University Hospital NHS Trust, Hucknall Road, Nottingham, NG5 1PB, UK

    Ian O. Ellis & Andrew R. Green

  3. Division of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Centre, Keck School of Medicine, Los Angeles, CA, 90033, USA

    Heinz-Josef Lenz

  4. Cancer Science Institute of Singapore, Centre for Life Sciences, 28 Medical Drive, #02-15, Singapore, Singapore

    Tingting Wang & Soo-Chin Lee

  5. Imperial College, Charing Cross Hospital, 1st Floor, E Wing, Fulham Palace Road, London, W6 8RF, UK

    Justin Stebbing

Authors
  1. Justin Stebbing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aleksandra Filipovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ian O. Ellis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew R. Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tanya Rapoz D’Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heinz-Josef Lenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Charles Coombes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tingting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Soo-Chin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Georgios Giamas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Justin Stebbing.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stebbing, J., Filipovic, A., Ellis, I.O. et al. LMTK3 expression in breast cancer: association with tumor phenotype and clinical outcome. Breast Cancer Res Treat 132, 537–544 (2012). https://doi.org/10.1007/s10549-011-1622-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1622-z

Keywords

Search

Navigation