title: Dicer Elicits Paclitaxel Chemosensitization and Suppresses Cancer Stemness in Breast Cancer by Repressing AXL.
abstract: Paclitaxel is a standard-of-care chemotherapy for breast cancer, despite the increasing recognition of its poor effectiveness in the treatment of patients with advanced disease. Here, we report that adenovirus-type 5 E1A-mediated elevation of the miRNA-processing enzyme Dicer is sufficient to enhance paclitaxel sensitization and reduce cancer stem-like cell properties in this setting. Elevating Dicer expression increased levels of the AXL kinase targeting miRNA miR-494, thereby repressing AXL expression to increase paclitaxel sensitivity. We found that Dicer expression was regulated at the transcription level by E1A, through activation of an MAPK14/CEBPα pathway. Our findings define a mechanism of E1A-mediated chemosensitization for paclitaxel, which is based upon the suppression of breast cancer stem-like cells, with potential implications for the diagnosis and treatment of breast cancer patients. Cancer Res; 76(13); 3916-28. ©2016 AACR.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Chang
authors.affiliation: Department of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hsin-An
authors.initials: HA
authors.lastname: Chen
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Chiu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chang
authors.affiliation: Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Tsang-Chih
authors.initials: TC
authors.lastname: Kuo
authors.affiliation: Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Tseng
authors.affiliation: Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Weu
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan. Department of Biotechnology, Asia University, Taichung, Taiwan. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan. Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan. jlsu@nhri.org.tw.
authors.forename: Jen-Liang
authors.initials: JL
authors.lastname: Su
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D043244:Ribonuclease III / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D017500:Adenovirus E1A Proteins; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C547168:MIRN494 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D048308:Mitogen-Activated Protein Kinase 14; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; D017239:Paclitaxel; D000094963:Axl Receptor Tyrosine Kinase