TY - JOUR AB - MicroRNA (miR)-106b~25 cluster regulates bypass of doxorubicin and γ-radiation induced senescence by downregulation of the E-cadherin transcriptional activator EP300. We asked whether upregulation of miR-106~25 cluster generates cells with a truly multidrug resistant (MDR) phenotype and whether this is due to upregulation of the ATP-binding cassette (ABC) transporter P-glycoprotein. We used minimally transformed mammary epithelial breast cancer cells (MTMECs) in which the miR-106b~25 cluster was experimentally upregulated by lentiviral transfection or in which hairpins targeting either EP300 or E-cadherin mRNAs have been expressed with lentiviruses. We find that overexpression of miR-106b~25 cluster led to the generation of MDR MTMECs (resistant to etoposide, colchicine and paclitaxel). Paclitaxel resistance was also studied after experimental downregulation of EP300 or E-cadherin. However none of these cells overexpressed P-glycoprotein or where able to efflux a fluorescent derivative of paclitaxel, making this phenotype drug-transporter independent. Paclitaxel treatment in MTMECs led to an increase in early apoptotic cells (Annexin V-positive), activation of caspase-9 and increase in the proportion of cells at the G2/M phase of the cell cycle. However, MTMEC overexpressing miR-106b~25 cluster, or with EP300 or E-cadherin downregulated, showed less activation of apoptosis, caspase-9 and caspase-3/-7 activities. Thus, miR-106b~25 cluster controls transporter-independent MDR by apoptosis evasion via downregulation of EP300. AD - The Third Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, P.R. China Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China Division of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK AU - Hu,Yunhui AU - Li,Kaiyong AU - Asaduzzaman,Muhammad AU - Cuella,Raquel AU - Shi,Hui AU - Raguz,Selina AU - Coombes,Raoul ,Charles AU - Zhou,Yuan AU - Yagüe,Ernesto DA - 2016/02/01 DO - 10.3892/or.2015.4412 EP - 1178 IS - 2 JO - Oncol Rep KW - paclitaxel P-glycoprotein apoptosis breast cancer PY - 2016 SN - 1021-335X 1791-2431 SP - 1170 ST - miR-106b~25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300 T2 - Oncology Reports TI - miR-106b~25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300 UR - https://doi.org/10.3892/or.2015.4412 VL - 35 ER -