title: The miR-106b~25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300.
abstract: Resistance to chemotherapeutic treatment, which is indirectly responsible for many cancer deaths, is normally associated with an aggressive phenotype including increased cell motility and acquisition of invasive properties. Here we describe how breast cancer cells overcome doxorubicin-induced senescence and become drug resistant by overexpression of the microRNA (miR)-106b~25 cluster. Although all three miRs in the cluster contribute to the generation of doxorubicin resistance, miR-25 is the major contributor to this phenotype. All three miRs in this cluster target EP300, a transcriptional activator of E-cadherin, resulting in cells acquiring a phenotype characteristic of cells undergoing epithelial-to-mesenchymal transition (EMT), including an increase in both cell motility and invasion, as well as the ability to proliferate after treatment with doxorubicin. These findings provide a novel drug resistance/EMT regulatory pathway controlled by the miR-106b~25 cluster by targeting a transcriptional activator of E-cadherin.
authors.affiliation: 1] State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China [2] Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: 1] State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China [2] Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK [3] Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.affiliation: MRC Prion Unit, University College London, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Jat
authors.affiliation: Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Li
authors.affiliation: Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Lombardo
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: D
authors.initials: D
authors.lastname: Xiong
authors.affiliation: Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
authors.affiliation: Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Raguz
authors.affiliation: Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Yagüe
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D050881:E1A-Associated p300 Protein / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000187:drug effects; D014162:Transfection
chemical_list: D015820:Cadherins; C542541:MIRN106 microRNA, human; D035683:MicroRNAs; D004317:Doxorubicin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human