Introduction: Basal-like (BL) breast cancer is an aggressive sub-type of breast cancer for which there is no targeted systemic therapy. C-Met is a receptor tyrosine kinase implicated in breast cancer. Clinical trials assessing the efficacy of anti-c-Met therapy are underway, yet few studies have analysed the clinical significance of c-Met expression and/or activation in breast cancer, in particular whether there is a correlation with molecular sub-type. The aims of this study are: 1) to establish the clinical significance of c-Met expression in invasive breast cancer, 2) evaluate the novel proximity ligation assay (PLA) as a method of measuring c-Met activation and 3) address the effect of hepatocyte growth factor (HGF)-mediated c-Met phosphorylation on migration and protein expression in cell lines representative of the BL sub-type. Methods: Immunohistochemistry for c-Met was performed on 1455 cases of breast cancer using tissue microarray (TMA) technology. The PLA was performed on TMAs constructed from 181 breast cancers. C-Met expression and the PLA product were correlated with clinico-pathological parameters and survival. The effects of HGF on cell migration and protein expression were assessed using migration assays, western blots and immunofluorescent studies. Results: C-Met expression was independently associated with BL breast cancer (odds ratio = 6.44, 95% confidence interval (CI) = 1.74-23.78, p = 0.005) and reduced overall survival (hazard ratio = 1.81, 95% CI = 1.07-3.06), p = 0.026). The PLA signal was not associated with molecular sub-type or survival. HGF stimulation was associated with a significant increase in BL cell migration (p < 0.01) but no evidence of epithelial-mesenchymal transition was observed. Conclusion: My findings suggest BL breast cancer patients should be included in future trials of anti-c-Met therapy. Further work is necessary to establish the prognostic utility of the PLA as a measure of c-Met activation and the mechanisms driving HGF-mediated cell migration.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:667323 |
| Date | January 2014 |
| Creators | Ho-Yen, Colan Maxwell |
| Publisher | Queen Mary, University of London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://qmro.qmul.ac.uk/xmlui/handle/123456789/8907 |
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