Prognostic Significance of Co-expression of RON and MET Receptors in Node-Negative Breast Cancer Patients

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Abstract
Purpose: RON and MET belong to a subfamily of tyrosine kinase receptors. They both can induce invasive growth, including migration, cell dissociation, and matrix invasion. Cross-linking experiments show that RON and MET form a noncovalent complex on the cell surface and cooperate in intracellular signaling. We wanted to examine the clinical significance of RON and MET expression patterns in node-negative breast cancer. Experimental Design: We studied the protein expressions of RON and MET in five breast cancer cell lines and a homogeneous cohort of 103 T1-2N0M0 breast carcinoma patients, including 52 patients with distant metastases and 51 patients with no evidence of disease after at least a 10-year follow-up. Results: Both HCC1937 and MDA-MB-231 cancer cell lines co-overexpressed RON and MET. The MCF-7 cell line did not express RON or MET. In multiple logistic regression analysis, RON expression (odds ratio, 2.6; P = 0.05) and MET expression (odds ratio, 4.7; P = 0.009) were independent predictors of distant relapse. RON+/MET+ and RON−/MET+ tumors resulted in a large risk increase for 10-year disease-free survival after adjusting for tumor size, histologic grade, estrogen receptor, bcl-2, HER-2/neu, and p53 status by multivariate Cox analysis (risk ratio, 5.3; P = 0.001 and risk ratio, 3.76; P = 0.005). The 10-year disease-free survival was 79.3% in patients with RON−/MET− tumors, was only 11.8% in patients with RON+/MET+ tumors, and was 43.9% and 55.6% in patients with RON−/MET+ and RON+/MET− tumors. Conclusions: Co-expression of RON and MET seems to signify an aggressive phenotype in node-negative breast cancer patients.