title: Lapatinib increases motility of triple-negative breast cancer cells by decreasing miRNA-7 and inducing Raf-1/MAPK-dependent interleukin-6.
abstract: Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. Nevertheless, its inhibitory effect on EGFR did not deliver clinical benefits for triple-negative breast cancer (TNBC) patients even EGFR overexpression was frequently found in this disease. Moreover, lapatinib was unexpectedly found to enhance metastasis of TNBC cells, but the underlying mechanisms are not fully understood. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6 antibody abolished the lapatinib-induced migration. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to induce IL-6 expression. Furthermore, our data showed that microRNA-7 directly binds and inhibits Raf-1 3'UTR activity, and that down-regulation of miR-7 by lapatinib contributes to the activation of Raf-1 signaling pathway and the induction of IL-6 expression. Our results not only revealed IL-6 as a key regulator of lapatinib-induced metastasis, but also explored the requirement of miR7/Raf-1/MAPK/AP-1 axis in lapatinib-induced IL-6 expression.
authors.affiliation: The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Hsiao
authors.affiliation: Department of Surgery, Chung-Shan Medical University, Taichung, Taiwan.
authors.forename: Ming-Hsin
authors.initials: MH
authors.lastname: Yeh
authors.affiliation: Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan.|Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Yun-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Ju-Fang
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.|Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
authors.affiliation: The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.|Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.|Center for Molecular Medicine, China Medical University and Hospital, Taichung, Taiwan.|Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D000077341:Lapatinib; D035683:MicroRNAs / Q000235:genetics*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D000077341:Lapatinib; D035683:MicroRNAs; D019950:Mitogen-Activated Protein Kinase 1; D019908:Proto-Oncogene Proteins c-raf; D011799:Quinazolines; D012333:RNA, Messenger; C508600:IL6 protein, human; C549242:MIRN7-1 microRNA, human
keywords: IL-6; Raf-1; lapatinib; microRNA; migration