Tumor angiogenesis and c-Met pathway activation - implications in breast cancer.

Breast cancer is a heterogeneous disease with wide range of clinical behaviour. Tumour angiogenesis and metastasis have been considered as prognostic markers of the breast carcinoma, and c-Met, a transmembrane receptor tyrosine kinase has been implicated in both these processes of tumour progression. This study was conducted to elucidate c-Met and downstream signalling pathways in breast cancer and correlate with angiogenesis as assessed by microvessel density (MVD) and other prognostic parameters including lymph node metastases. Microvessel density (MVD) was assessed by endothelial cell (CD34) marker in breast cancers. c-Met was evaluated by immunohistochemistry for protein expression and by copy number assay for amplification at gene level. PCR array for gene expression related to c-Met, RAS-MAPK, PI3K-AKT and angiogenesis pathway was performed by real-time PCR. c-Met protein, copy number and mRNA expression did not differ significantly with the lymph node status or MVD. However, Her-2 overexpressing group showed c-Met protein overexpression and amplification. c-Met protein overexpression was also noted in the Luminal B subtype though no amplification was noted. Thus, the c-Met immunohistochemistry score and the c-MET copy numbers did not correlate with each other. c-Met downstream pathway genes (RAS-MAPK, PI3K-AKT and angiogenesis pathway) showed significant upregulation in Luminal B molecular subtype, lymph node-positive cases and cases with high MVD. The downstream signalling pathways (angiogenesis, RAS-MAPK and PI3K-AKT) were associated high MVD, lymph node metastases, and Her-2 and Luminal B subtype. Since inhibitors of these pathways are commercially available, these can be of therapeutic significance.