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

Departments of ¹ Pathology, ² Radiation Oncology, ³ Internal Medicine, ⁴ Surgery, and ⁵ Environmental and Occupational Health and Institutes of ⁶ Molecular Medicine, College of Medicine, National Cheng Kung University, and⁷ Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan

Requests for reprints: Wen-Ying Lee, Department of Pathology, Chi Mei Medical Center, 901 Chung Hwa Road, Yung Kang City, Tainan 710, Taiwan. Fax: 886-6-2746411; E-mail: 7707{at}so-net.net.tw.

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_1-2N₀M₀ 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.

Key Words: RON • MET • node-negative breast cancer • Tumor Progression, Invasion, and Metastasis • Breast cancer

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