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

• Published in: Clinical cancer research Vol. 11; no. 6; pp. 2222 - 2228
• Main Authors: LEE, Wen-Ying, CHEN, Helen H. W, CHOW, Nan-Haw, SU, Wu-Chou, LIN, Pin-Wen, GUO, How-Ran
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.03.2005
• Subjects: Adult; Aged; Antineoplastic agents; Biological and medical sciences; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cohort Studies; Female; Hepatocyte Growth Factor - metabolism; Humans; Lymph Nodes - pathology; Medical sciences; MET; Middle Aged; Neoplasm Invasiveness - pathology; Neoplasms, Ductal, Lobular, and Medullary - metabolism; Neoplasms, Ductal, Lobular, and Medullary - secondary; node-negative breast cancer; Pharmacology. Drug treatments; Prognosis; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-met; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - metabolism; Receptors, Growth Factor - metabolism; RON; Survival Rate; Tumor Cells, Cultured; Tumor Progression, Invasion, and Metastasis; Tumor Suppressor Protein p53 - metabolism; Human; Mammary gland diseases; Prognosis; Breast cancer; Malignant tumor; Gene expression; Biological receptor
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-1761

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 T 1-2 N 0 M 0 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.