Breast Cancer Research and Treatment

, Volume 122, Issue 1, pp 105–110 | Cite as

The complete family of epidermal growth factor receptors and their ligands are co-ordinately expressed in breast cancer

  • Emmet McIntyre
  • Edith Blackburn
  • Philip J. Brown
  • Colin G. Johnson
  • William J. Gullick
Preclinical study

Abstract

The levels of expression of the four receptors and eleven ligands composing the epidermal growth factor family were measured using immunohistochemical staining in one hundred cases of breast cancer. All of the family were expressed to some degree in some cases; however, individual cases showed a very wide range of expression of the family from essentially none to all the factors at high levels. The highest aggregate level of expression of a receptor was HER2 followed by HER1, then HER3, then HER4. The ligands (including two splice variants of the NRG1 and NRG2 genes) broadly fell into three groups, those with the highest aggregate expression were Epigen, Epiregulin, Neuregulin 1α, Neuregulin 2α, Neuregulin 2β, Neuregulin 4 and TGFα, moderate expression was seen with EGF, Neuregulin 1β and Neuregulin 3, and relatively low levels of expression were seen of HB-EGF, Betacellulin and Amphiregulin. Statistical analysis using Spearman’s Rank Correlation showed a positive correlation of expression between each of the factors. Analysing the data using the Cox Proportional Hazards model showed that, in this dataset, the most powerful predictors of relapse free interval and overall survival were the combined measurement of only Epigen and Neuregulin 4.

Keywords

ErbB Growth factor Growth factor receptor Prognosis Breast cancer 

Supplementary material

10549_2009_536_MOESM1_ESM.pdf (43 kb)
Supplementary material 1 (PDF 42 kb)

References

  1. 1.
    Stein RA, Staros JV (2006) Insights into the evolution of the ErbB receptor family and their ligands from sequence analysis. BMC Evol Biol 6:79CrossRefPubMedGoogle Scholar
  2. 2.
    Hayes NV, Gullick WJ (2008) The Neuregulin family of genes and their multiple splice variants in breast cancer. J Mammary Gland Biol Neoplasia 13:205–214CrossRefPubMedGoogle Scholar
  3. 3.
    Sundvall M, Iljin K, Kilpinen S, Sara H, Kallioniemi OP, Elenius K (2008) Role of ErbB4 in breast cancer. J Mammary Gland Biol Neoplasia 13:259–268CrossRefPubMedGoogle Scholar
  4. 4.
    Lemmon MA (2009) Ligand-induced receptor dimerisation. Exp Cell Res 315:638–648Google Scholar
  5. 5.
    Johnson CG, Goldman JP, Gullick WJ (2004) Simulating intracellular processes using object-oriented computational modelling. Prog Biophys Mol Biol 86:379–406CrossRefPubMedGoogle Scholar
  6. 6.
    Scaltriti M, Baselga J (2006) The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 12:5268–5272CrossRefPubMedGoogle Scholar
  7. 7.
    Kochupurakkai BS, Harari D, Di-Segni A, Maik-Rachline G, Lyass L, Gur G, Kerber G, Citri A, Lavi S, Eilam R, Chalifa-Caspi V, Eshhar Z, Pikarsky E, Pinkas-Kramarski R, Bacuss SS, Yarden Y (2005) Epigen the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity. J Biol Chem 280:8503–8512CrossRefGoogle Scholar
  8. 8.
    Toyoda H, Komurasaki T, Uchida D, Takayama Y, Isobe T, Okuyama Y, Hanada K (1995) Epiregulin: A novel epidermal growth factor with mitogenic activity for rat primary hepaocytes. J Biol Chem 270:7495–7500CrossRefPubMedGoogle Scholar
  9. 9.
    Gullick WJ, Marsden JJ, Whittle N, Ward B, Bobrow L, Waterfield MD (1986) Expression of epidermal growth factor receptors on cervical, ovarian and vulval carcinomas. Cancer Res 46:285–292PubMedGoogle Scholar
  10. 10.
    Gullick WJ, Berger MS, Bennett PLP, Rothbard JB, Waterfield MD (1987) Expression of the c-erbB-2 protein in normal and transformed cells. Int J Cancer 40:246–254CrossRefPubMedGoogle Scholar
  11. 11.
    Rajkumar T, Majhi U, Malligarjuna V, Shantha V, Gullick WJ (1995) Prevalence of c-erbB-3 expression in squamous cell carcinomas of the cervix as determined by the monoclonal antibody RTJ-2. Int J Oncol 6:105–109Google Scholar
  12. 12.
    Srinivasan R, Poulsom R, Hurst HC, Gullick WJ (1998) Expression of the HER4/c-erbB-4 protein and mRNA in normal human fetal and adult tissues and in a survey of nine solid tumour types. J Pathol 185:236–245CrossRefPubMedGoogle Scholar
  13. 13.
    Saeki T, Qi C-F, Johnson G, Gullick WJ, Tahara E, Normanno N, Ciardiello F, Kenney N, Stromberg K, Salomon DS (1992) Differential immunohistochemical detection of amphiregulin and cripto in normal and malignant human colon. Cancer Res 52:3467–3473PubMedGoogle Scholar
  14. 14.
    Chobotava K, Spyropolou I, Carver J, Manek S, Heath JK, Gullick WJ, Barlow DH, Sargent IL, Mardon HJ (2002) Heparin binding epidermal growth factor and its receptors mediate implantation of the human blastocyst. Mech Dev 119:137–144CrossRefGoogle Scholar
  15. 15.
    Srinivasan R, Benton E, McCormick F, Gullick WJ (1999) Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 growth factor receptors and their ligands, neuregulin-1 alpha, neuregulin-1 beta and Betacellulin, in normal endometrium and endometrial cancer. Clin Cancer Res 5:2877–2883PubMedGoogle Scholar
  16. 16.
    Normanno N, Qi C-F, Gullick WJ, Persico G, Yarden Y, Wen D, Plowman G, Kenny N, Johnson G, Kim N, Brandt R, Soarez I, Dickson RB, Salomon DS (1993) Expression of Amphiregulin, cripto-1 and Heregulin alpha in human breast cancer cells. Int J Oncol 2:903–911Google Scholar
  17. 17.
    Dunn M, Sinha P, Campbell R, Blackburn E, Levinson N, Rampaul R, Bates T, Humphreys S, Gullick W (2004) Co-expression of Neuregulin 1, 2, 3 and 4 in human breast cancer. J Pathol 203:672–680CrossRefPubMedGoogle Scholar
  18. 18.
    Hayes NVL, Blackburn E, Smart LV, Boyle M, Russell G, Frost T, Morgan B, Baines AJ, Gullick WJ (2007) Identification and characterisation of novel spliced variants of NRG4 in prostate cancer. Clin Cancer Res 13:3147–3155CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Emmet McIntyre
    • 1
  • Edith Blackburn
    • 2
  • Philip J. Brown
    • 3
  • Colin G. Johnson
    • 1
  • William J. Gullick
    • 2
  1. 1.Computing LaboratoryUniversity of KentCanterburyUK
  2. 2.Department of BiosciencesUniversity of KentCanterburyUK
  3. 3.Institute of Mathematics, Statistics and Actuarial ScienceUniversity of KentCanterburyUK

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