EGF Receptor in Breast Cancer: Its Quantification and Role in Invasion

Robertson, Kevin William (1999) EGF Receptor in Breast Cancer: Its Quantification and Role in Invasion. MD thesis, University of Glasgow.

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EGF receptor was first implicated in the prognosis of breast cancer patients in 1987. It has since been extensively studied, both in terms of its clinical significance and its role in tumour biology. Despite this, the mechanism of its prognostic influence remains unclear, as is its relationship with established prognostic indicators. Inaccuracies in the methods used to measure receptor expression may, in part, be responsible. This thesis addresses this issue, and then broaches the possibility that receptor mediated tumour cell invasion might account for its effect on prognosis. Receptor measurement using a quantitative radioimmunohistochemical assay (Rihc) was compared with the most commonly used conventional methods. Using Rihc, receptor could be measured in 92% of tumours, as opposed to 38% and 42%, with ligand binding (Lb) and conventional immunohistochemistry (Cihc), respectively. The conventional methods, categorising tumours as positive or negative, showed a high level of correlation (p=0.0006) but for 26% of the tumours did not concur. This level of disparity may account for some of the confusion over the role of EGF receptor in breast cancer. Rihc was compared with the other methods using a Spearman rank analysis. Limiting this analysis to tumours receptor positive using the conventional technique, Rihc and Cihc had a better correlation (p<0.0005), than Rihc and Lb (p=0.702). Despite the correlation between the immunohistochemical methods, Cihc failed to detect receptor in 52% of the tumours, a group in which receptor expression varied by 10 fold using Rihc. Overall, Rihc proved more sensitive and more accurate. In total, 203 breast cancers were analysed using Rihc. The vast majority (98%) had levels of receptor below those in normal (reduction mammoplasty) breast. In keeping with the consensus, there was a strong inverse correlation between EGF receptor and oestrogen receptor (p<0.0005). There was also a direct association with poorer histological grade (p=0.005), but none to either T-stage (p=0.392) or nodal status (p=0.074). Additionally, the accuracy of Rihc allowed identification of an inverse correlation between the levels of oestrogen and EGF receptor (rank analysis p=0.032), and also a direct correlation with maximal tumour size, in millimetres (rank analysis p=0.049). To assess the relationship with outcome, tumours were divided into groups determined by receptor expression. Using a univariate analysis, EGF receptor predicted death (from all causes) and also disease free survival; tumours studied 2 groups (p=0.0429, p=0.0446, respectively), 3 groups (p=0.0047, p=0.0072, respectively), and 4 groups (p=0.0009, p=0.0013, respectively). However, in multivariate analysis, oestrogen receptor (relative risk 4.7, 95%CI 2.5-8.7), then nodal status (relative risk 3.0, 95%CI 1.6-5.7), followed by tumour size (TNM) (relative risk 1.8, 95%CI 1.1- 2.8), were included in the outcome model for all deaths, and EGF receptor was the least significant predictor of outcome. It has been hypothesised that EGF receptor signalling promotes tumour cell motility and invasion. A novel invasion assay, using the basement membrane substitute Matrigel, was developed and applied to breast cancer cell lines expressing a range of receptor densities. Invasion, into the Matrigel layer, was promoted by EGF and ascertained using confocal microscopy coupled to image analysis. The MDA-MB-231 cell line invaded up to 30|am, with a clear dose response curve (p=0.0005). Invasion, also evident for the MCF7 Adriamycin resistant and BT20 cell lines, did not simply reflect proliferation. It occurred more frequently in the cell lines expressing more EGF receptor, but this relationship was not absolute, indicating that other factors were important. Monoclonal antibody, ICR 16, directed to the EGF receptor and inhibiting EGF binding abrogated invasion, as did the tyrosine kinase inhibitor, 4,5-Dianilinophthalimide (DAPH). These results indicated that breast tumour cell invasion was, at least partly, modulated by EGF receptor.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Peter Stanton
Keywords: Oncology
Date of Award: 1999
Depositing User: Enlighten Team
Unique ID: glathesis:1999-74936
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Sep 2019 15:06
Last Modified: 27 Sep 2019 15:06

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