miR-302b enhances breast cancer cell sensitivity to cisplatin by regulating E2F1 and the cellular DNA damage response

Abstract

// Alessandra Cataldo 1,2 , Douglas G. Cheung 1 , Andrea Balsari 2,3 , Elda Tagliabue 3 , Vincenzo Coppola 1 , Marilena V. Iorio 4 , Dario Palmieri 1 and Carlo M. Croce 1 1 Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine and Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA 2 Department of Biomedical Sciences for Health, University of Milan, Milan, Italy 3 Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Milan, Italy 4 Start Up Unit, Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Milan, Italy Correspondence to: Carlo M. Croce, email: // Dario Palmieri, email: // Keywords : breast cancer, miR-302b, cisplatin, E2F1, ATM, DDR Received : October 29, 2015 Accepted : November 10, 2015 Published : November 25, 2015 Abstract The identification of the molecular mechanisms involved in the establishment of the resistant phenotype represents a critical need for the development of new strategies to prevent or overcome cancer resistance to anti-neoplastic treatments. Breast cancer is the leading cause of cancer-related deaths in women, and resistance to chemotherapy negatively affects patient outcomes. Here, we investigated the potential role of miR-302b in the modulation of breast cancer cell resistance to cisplatin. miR-302b overexpression enhances sensitivity to cisplatin in breast cancer cell lines, reducing cell viability and proliferation in response to the treatment. We also identified E2F1, a master regulator of the G1/S transition, as a direct target gene of miR-302b. E2F1 transcriptionally activates ATM, the main cellular sensor of DNA damage. Through the negative regulation of E2F1, miR-302b indirectly affects ATM expression, abrogating cell-cycle progression upon cisplatin treatment. Moreover miR-302b, impairs the ability of breast cancer cells to repair damaged DNA, enhancing apoptosis activation following cisplatin treatment. These findings indicate that miR-302b plays a relevant role in breast cancer cell response to cisplatin through the modulation of the E2F1/ATM axis, representing a valid candidate as therapeutic tool to overcome chemotherapy resistance.