miR-671-5p inhibits epithelial-to-mesenchymal transition by downregulating FOXM1 expression in breast cancer

// Xiaohui Tan 1 , Yebo Fu 1 , Liang Chen 1 , Woojin Lee 1 , Yinglei Lai 2 , Katayoon Rezaei 3 , Sana Tabbara 3 , Patricia Latham 3 , Christine B. Teal 4 , Yan-Gao Man 5 , Robert S. Siegel 6 , Rachel F. Brem 7 , Sidney W. Fu 1 1 Department of Medicine (Division of Genomic Medicine), The George Washington University School of Medicine and Health Sciences, Washington, DC, USA 2 Department of Statistics, The George Washington University, Washington, DC, USA 3 Department of Pathology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA 4 Department of Surgery, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA 5 Research Lab and International Collaboration, Bon Secours Cancer Institute, Bon Secours Health System, Richmond, VA, USA 6 Department of Medicine (Division of Hematology/Oncology), The George Washington University School of Medicine and Health Sciences, Washington, DC, USA 7 Department of Radiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA Correspondence to: Sidney W. Fu, e-mail: sfu@gwu.edu Keywords: breast cancer, miR-671-5p, tumor suppressor, FOXM1, EMT Received: August 31, 2015     Accepted: November 11, 2015     Published: November 18, 2015 ABSTRACT MicroRNA (miRNA) dysfunction is associated with a variety of human diseases, including cancer. Our previous study showed that miR-671-5p was deregulated throughout breast cancer progression. Here, we report for the first time that miR-671-5p is a tumor-suppressor miRNA in breast tumorigenesis. We found that expression of miR-671-5p was decreased significantly in invasive ductal carcinoma (IDC) compared to normal in microdissected formalin-fixed, paraffin-embedded (FFPE) tissues. Forkhead Box M1 (FOXM1), an oncogenic transcription factor, was predicted as one of the direct targets of miR-671-5p, which was subsequently confirmed by luciferase assays. Forced expression of miR-671-5p in breast cancer cell lines downregulated FOXM1 expression, and attenuated the proliferation and invasion in breast cancer cell lines. Notably, overexpression of miR-671-5p resulted in a shift from epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) phenotypes in MDA-MB-231 breast cancer cells and induced S-phase arrest. Moreover, miR-671-5p sensitized breast cancer cells to cisplatin, 5-fluorouracil (5-FU) and epirubicin exposure. Host cell reactivation (HCR) assays showed that miR-671-5p reduces DNA repair capability in post-drug exposed breast cancer cells. cDNA microarray data revealed that differentially expressed genes when miR-671-5p was transfected are associated with cell proliferation, invasion, cell cycle, and EMT. These data indicate that miR-671-5p functions as a tumor suppressor miRNA in breast cancer by directly targeting FOXM1. Hence, miR-671-5p may serve as a novel therapeutic target for breast cancer management.