c-Met is a receptor tyrosine kinase that upon binding of its ligand, hepatocyte growth factor (HGF), activates downstream pathways with diverse cellular functions that are important in organ development and cancer progression. Anomalous c-Met signalling has been described in a variety of cancer types, and the receptor is regarded as a novel therapeutic target. In breast cancer there is a need to develop new treatments, particularly for the aggressive subtypes such as triple-negative and basal-like cancer, which currently lack targeted therapy. Over the last two decades, much has been learnt about the functional role of c-Met signalling in different models of breast development and cancer. This work has been complemented by clinical studies, establishing the prognostic significance of c-Met in tissue samples of breast cancer. While the clinical trials of anti-c-Met therapy in advanced breast cancer progress, there is a need to review the existing evidence so that the potential of these treatments can be better appreciated. The aim of this article is to examine the role of HGF/c-Met signalling in in vitro and in vivo models of breast cancer, to describe the mechanisms of aberrant c-Met signalling in human tissues, and to give a brief overview of the anti-c-Met therapies currently being evaluated in breast cancer patients. We will show that the HGF/c-Met pathway is associated with breast cancer progression and suggest that there is a firm basis for continued development of anti-c-Met treatment, particularly for patients with basal-like and triple-negative breast cancer.

Purpose: To investigate how biologically relevant markers change in response to antiangiogenic therapy in metastatic clear cell renal cancer (mRCC) and correlate these changes with outcome.Experimental Design: The study used sequential tumor tissue and functional imaging (taken at baseline and 12-16 weeks) obtained from three similar phase II studies. All three studies investigated the role of VEGF tyrosine kinase inhibitors (TKI) before planned nephrectomy in untreated mRCC (n ¼ 85). The effect of targeted therapy on ten biomarkers was measured from sequential tissue. Comparative genomic hybridization (CGH) array and DNA methylation profiling (MethylCap-seq) was performed in matched frozen pairs. Biomarker expression was correlated with early progression (progression as best response) and delayed progression (between 12-16 weeks).Results: VEGF TKI treatment caused a significant reduction in vessel density (CD31), phospho-S6K expression, PDL-1 expression, and FOXP3 expression (P < 0.05 for each). It also caused a significant increase in cytoplasmic FGF-2, MET receptor expression in vessels, Fuhrman tumor grade, and Ki-67 (P < 0.05 for each). Higher levels of Ki-67 and CD31 were associated with delayed progression (P < 0.05). Multiple samples (n ¼ 5) from the same tumor showed marked heterogeneity of tumor grade, which increased significantly with treatment. Array CGH showed extensive intrapatient variability, which did not occur in DNA methylation analysis.Conclusion: TKI treatment is associated with dynamic changes in relevant biomarkers, despite significant heterogeneity in chromosomal and protein, but not epigenetic expression. Changes to Ki-67 expression and tumor grade indicate that treatment is associated with an increase in the aggressive phenotype of the tumor.

BACKGROUND: Basal-like (BL) breast cancer is an aggressive form of breast cancer with limited treatment options. Recent work has identified BL breast cancer as a biologically distinct form of triple-negative breast cancer, with a worse outlook. The receptor tyrosine kinase c-Met is a novel therapeutic target associated with reduced survival in breast cancer. Few studies have specifically addressed the association between c-Met and molecular subtype of breast cancer, yet this is a key consideration when selecting patients for clinical trials. The aim of this study is to evaluate c-Met expression in a large cohort of invasive breast cancers and in particular, its correlation with molecular subtype. METHODS: Immunohistochemistry for c-Met was performed and evaluated on 1274 invasive breast cancers using tissue microarray technology. The c-Met scores were correlated with molecular subtype, survival, and other standard clinicopathological prognostic factors. RESULTS: Multivariate logistic regression showed c-Met was independently associated with BL status (odds ratio 5 6.44, 95% confidence interval 5 1.74-23.78, P 5.005). There was a positive correlation between c-Met and Her2 (P 5.005) and an inverse correlation with tumor size (P <.001). C-Met was an independent poor prognostic factor at Cox regression analysis in all subtypes (hazard ratio 5 1.85, 95% confidence interval 5 1.07-3.19, P 5.027) and there was a trend toward reduced survival in BL tumors overexpressing c-Met, but this was not significant. CONCLUSIONS: C-Met is independently associated with BL breast cancer. In the future, patients with BL tumors should be included in clinical trials of anti-c-Met therapy. Cancer 2014;120:163-71.