title: Targeting of miR34a-NOTCH1 axis reduced breast cancer stemness and chemoresistance.
abstract: Human breast cancers include cancer stem cell populations as well as nontumorigenic cancer cells. Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. miRNAs regulate the expression of many target genes; therefore, dysregulation of miRNAs has been associated with the pathogenesis of human diseases, including cancer. However, a role for miRNA dysregulation in stemness and drug resistance has yet to be identified. Members of the miR34 family are reportedly tumor-suppressor miRNAs and are associated with various human cancers. Our results confirm that miR34a expression was downregulated in MCF7/ADR cells compared with MCF7 cells. We hypothesized that this reduction was due to the p53 (TP53) mutation in MCF7/ADR cells. In this study, we found that primary and mature miR34a were suppressed by treatment with p53 RNAi or the dominant-negative p53 mutant in MCF7 cells. Ectopic miR34a expression reduced cancer stem cell properties and increased sensitivity to doxorubicin treatment by directly targeting NOTCH1. Furthermore, tumors from nude mice treated with miR34a were significantly smaller compared with those of mice treated with control lentivirus. Our research suggests that the ectopic expression of miR34a represents a novel therapeutic approach in chemoresistant breast cancer treatment.
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Park
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: EunSun
authors.initials: E
authors.lastname: Chang
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyeok-Gu
authors.initials: HG
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Chun
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Woo
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Hyun Kyung
authors.initials: HK
authors.lastname: Kong
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Je Yeong
authors.initials: JY
authors.lastname: Ko
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Breast Surgery, Sun Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou, Peoples Republic of China. parkjh@sookmyung.ac.kr songerwei02@yahoo.com.cn.
authors.forename: Erwei
authors.initials: E
authors.lastname: Song
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea. parkjh@sookmyung.ac.kr songerwei02@yahoo.com.cn.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin