title: Combined inhibition of EGFR and c-ABL suppresses the growth of triple-negative breast cancer growth through inhibition of HOTAIR.
abstract: Triple-negative breast cancer (TNBC) does not express conventional therapeutic targets and is the only type of malignant breast cancer for which no designated FDA-approved targeted therapy is available. Although overexpression of epidermal growth factor receptor (EGFR) is frequently found in TNBC, the therapeutic effect of EGFR inhibitors in TNBC has been underwhelming. Here we show that co-treatment with clinically validated inhibitors of c-ABL (imatinib) and EGFR (lapatinib) results in synergistic growth inhibition in TNBC cells. The dual treatment leads to synergistic repression of the long non-coding RNA (lncRNA) HOTAIR (HOX Antisense Intergenic RNA). HOTAIR has been known to induce tumor growth and metastasis in breast cancer. Depleting HOTAIR alone phenocopies the dual treatment in growth suppression. We show that expression of HOTAIR is regulated by β-catenin through a LEF1/TCF4-binding site. The dual treatment blocks nuclear expression of β-catenin and prevents its recruitment to the HOTAIR promoter. Consistently, forced expression of β-catenin rescued HOTAIR expression and cell viability in the presence of both drugs. Upregulation of HOTAIR is associated with TNBC in cell lines and a cohort of primary tumors. This study elucidates a previously unidentified mechanism in TNBC linking signaling with lncRNA regulation which may be exploited for therapeutic gain.
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Yuan-Liang
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Overstreet
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Min-Shan
authors.initials: MS
authors.lastname: Chen
authors.affiliation: Department of Pathology & Lab Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|School of Pharmacy, Zhejiang Chinese Medical University, Zhejiang, China.
authors.forename: Hua-Jun
authors.initials: HJ
authors.lastname: Zhao
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Ho
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Cancer and Cell Biology Graduate Program, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Smith
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Cancer and Cell Biology Graduate Program, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C561566:HOTAIR long untranslated RNA, human; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; C512478:EGFR protein, human; D066246:ErbB Receptors; D016315:Proto-Oncogene Proteins c-abl
keywords: EGFR; b-catenin; breast cancer; c-ABL; lncRNA