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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Explore related subjects
Discover the latest articles and news from researchers in related subjects, suggested using machine learning.References
Stein RA, Staros JV (2006) Insights into the evolution of the ErbB receptor family and their ligands from sequence analysis. BMC Evol Biol 6:79
Hayes NV, Gullick WJ (2008) The Neuregulin family of genes and their multiple splice variants in breast cancer. J Mammary Gland Biol Neoplasia 13:205–214
Sundvall M, Iljin K, Kilpinen S, Sara H, Kallioniemi OP, Elenius K (2008) Role of ErbB4 in breast cancer. J Mammary Gland Biol Neoplasia 13:259–268
Lemmon MA (2009) Ligand-induced receptor dimerisation. Exp Cell Res 315:638–648
Johnson CG, Goldman JP, Gullick WJ (2004) Simulating intracellular processes using object-oriented computational modelling. Prog Biophys Mol Biol 86:379–406
Scaltriti M, Baselga J (2006) The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 12:5268–5272
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 280:8503–8512
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 270:7495–7500
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 46:285–292
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 40:246–254
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 6:105–109
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 185:236–245
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 52:3467–3473
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 119:137–144
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 5:2877–2883
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 2:903–911
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 203:672–680
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 13:3147–3155
Acknowledgments
We are grateful to Professor Adrian Harris and Dr Russell Leek for the tissue array samples. Edith Blackburn is supported by a grant from the E. B. Hutchinson Trust.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
McIntyre, E., Blackburn, E., Brown, P.J. et al. The complete family of epidermal growth factor receptors and their ligands are co-ordinately expressed in breast cancer. Breast Cancer Res Treat 122, 105–110 (2010). https://doi.org/10.1007/s10549-009-0536-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-009-0536-5