Role of MRE11 in Cell Proliferation, Tumor Invasion, and DNA Repair in Breast Cancer

Abstract

Previous studies have shown that altered forms of MRE11, a protein known to play a vital role in DNA double-strand break repair, DNA replication, and telomere maintenance are associated with cancer outcomes. We investigated the role of MRE11 in breast cancer in both clinical and in vitro settings. We examined MRE11 expression in tumor tissues from invasive ductal carcinoma breast cancer patients (n = 254) by immunohistochemistry, and associations with clinicopathological characteristics and overall survival were assessed using Cox proportional hazards regression models and Kaplan-Meier survival curves. Effect of MRE11 overexpression and knockdown on cell proliferation, invasion, and radioresistance was assessed in vitro using breast cancer cell lines (MCF-7 and MDA-MB-231). We also investigated the mechanisms involved. Effect of MRE11 overexpression on tumor growth was assessed in an orthotopic xenograft model (n = 8 mice per group). All statistical tests were two-sided. Of the 254 tissue samples, 69.3% and 30.7% showed high and low MRE11 expression, respectively. High MRE11 expression was statistically significantly associated with malignant cancer behavior compared with low MRE11 expression (eg, stages III and IV vs stage I, P = .004; poor overall survival, P = .005). MRE11 overexpression in breast cancer cell lines promoted cell proliferation through STAT3, cell cycle entry, invasion and migration, and radioresistance via enhanced DNA repair activity and also inhibited apoptosis; knockdown of MRE11 had the opposite effect. In xenograft tumor-bearing mice (n = 8 per group), increased tumor growth was observed in the MRE11-overexpressing group compared with the control group (tumor volume at week 8, control vs MRE11-overexpressing tumor originating from MCF-7 cells, mean = 280.4 mm(3), 95% confidence interval [CI] = 62.4 to 498.4 mm(3) vs mean = 631.0 mm(3), 95% CI = 296.9 to 965.0 mm(3), P = .043). High MRE11 expression was associated with a more malignant behavior in breast cancer. MRE11 may be a novel oncoprotein and may therefore serve as a new therapeutic intervention against breast cancer.