title: miR-302b enhances breast cancer cell sensitivity to cisplatin by regulating E2F1 and the cellular DNA damage response.
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.
authors.affiliation: 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.|Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cataldo
authors.affiliation: 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.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Cheung
authors.affiliation: Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.|Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Balsari
authors.affiliation: Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Milan, Italy.
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
authors.affiliation: 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.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
authors.affiliation: Start Up Unit, Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Milan, Italy.
authors.forename: Marilena V
authors.initials: MV
authors.lastname: Iorio
authors.affiliation: 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.
authors.forename: Dario
authors.initials: D
authors.lastname: Palmieri
authors.affiliation: 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.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C532169:MIRN302A microRNA, human; D035683:MicroRNAs; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D053148:Caspase 3; D053179:Caspase 7; D002945:Cisplatin
keywords: ATM; DDR; E2F1; breast cancer; cisplatin; miR-302b