title: Loss of microRNA-27b contributes to breast cancer stem cell generation by activating ENPP1.
abstract: Cancer stem cells (CSCs) have been identified in various types of cancer; however, the mechanisms by which cells acquire CSC properties such as drug resistance and tumour seeding ability are not fully understood. Here, we identified microRNA-27b (miR-27b) as a key regulator for the generation of a side-population in breast cancer cells that showed CSC properties, and also found that the anti-type II diabetes (T2D) drug metformin reduced this side-population via miR-27b-mediated repression of ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1), which is involved in T2D development. ENPP1 induced the generation of the side-population via upregulation of the ABCG2 transporter. ENPP1 was also identified as a substrate of the 26S proteasome, the activity of which is downregulated in CSCs. Overall, these results demonstrate that a T2D-associated gene plays an important role in tumour development and that its expression is strictly controlled at the mRNA and protein levels.
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Tokyo 104-0045, Japan.
authors.forename: Ryou-u
authors.initials: RU
authors.lastname: Takahashi
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Tokyo 104-0045, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyazaki
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Tokyo 104-0045, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Takeshita
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Tokyo 104-0045, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Genomic Application Group, Japan Diagnostics and Genomics, Agilent Technologies Japan Ltd., 9-1, Tokyo 192-8510, Japan.
authors.forename: Kaho
authors.initials: K
authors.lastname: Minoura
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Tokyo 104-0045, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Ono
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Tokyo 104-0045, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodaira
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Tokyo 104-0045, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Gastroenterological Surgery, Graduated School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Tokyo 104-0045, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D015536:Down-Regulation; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D043823:Taxoids; D000077143:Docetaxel; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases