Abstract 3011: Two-sided story of DNA repair proteins MRE11 and RAD51 in breast cancer

Abstract

Abstract Background DNA repair proteins are required for the maintenance of genome integrity in normal cells. However previous studies also showed that altered expression of MRE11 and RAD51, proteins crucial for DNA double-strand break repair, DNA replication, and telomere maintenance, are associated with cancer outcomes. In this study, we investigated the role of MRE11 and RAD51 in breast cancer in both clinical and in vitro settings. Methods The expression of MRE11 and RAD51 in breast tumor tissues were determined by immunohistochemistry, and associations with clinicopathological characteristics and overall survival were assessed using Cox proportional hazards regression models and Kaplan-Meier survival curves. The effect of altered expression of MRE11 and RAD51 on cell proliferation, invasion, and treatment resistance was assessed in vitro using breast cancer cell lines, with the underlying mechanisms explored. The effect of MRE11 and RAD51 overexpression on tumor growth was assessed in an orthotopic xenograft model. All statistical tests were two-sided. Results High MRE11 expression was statistically significantly associated with malignant cancer behaviors including increased tumor size and lymph node metastasis as well as resistance to radiotherapy and chemotherapy. 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, tumor growth was increased in MRE11-overexpressing group. RAD51 was expressed both in the cytoplasm and nucleus of all the breast cancer and non-cancerous cell lines. Expression levels of cytoplasmic RAD51 were positively correlated with cancer stage, tumor size, lymph node metastasis in breast cancer patients. High expression of cytoplasmic RAD51 predicted a poor patient survival as well as resistance to radiotherapy and chemotherapy. Conclusion High MRE11 and RAD51 expression was associated with a more malignant behavior in breast cancer. MRE11 and RAD51 may serve as potential targets for therapeutic intervention against breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Shyng-Shiou F. Yuan, Amos Hung, Ming-Feng Hou. Two-sided story of DNA repair proteins MRE11 and RAD51 in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3011. doi:10.1158/1538-7445.AM2015-3011