title: Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells.
abstract: Distant relapse after chemotherapy is an important clinical issue for treating breast cancer patients and results from the development of cancer stem-like cells (CSCs) during chemotherapy. Here we report that blocking epithelial-to-mesenchymal transition (EMT) suppresses paclitaxel-induced CSCs properties by using a MDA-MB-231-xenografted mice model (in vivo), and breast cancer cell lines (in vitro). Paclitaxel, one of the cytotoxic taxane-drugs such as docetaxel, increases mesenchymal markers (Vimentin and Fibronectin) and decreases an epithelial marker (Zo-1). Blocking TGF-β signaling with the TGF-β type I receptor kinase (ALK5) inhibitor, EW-7197, suppresses paclitaxel-induced EMT and CSC properties such as mammosphere-forming efficiency (MSFE), aldehyde dehydrogenase (ALDH) activity, CD44+/CD24- ratio, and pluripotency regulators (Oct4, Nanog, Klf4, Myc, and Sox2). The combinatorial treatment of EW-7197 improves the therapeutic effect of paclitaxel by decreasing the lung metastasis and increasing the survival time in vivo. We confirmed that Snail is increased by paclitaxel-induced intracellular reactive oxygen species (ROS) and EW-7197 suppresses the paclitaxel-induced Snail and EMT by attenuating paclitaxel-induced intracellular ROS. Knock-down of SNAI1 suppresses paclitaxel-induced EMT and CSC properties. These data together suggest that blocking the Snail-induced EMT with the ALK5 inhibitor attenuates metastasis after paclitaxel-therapy and that this combinatorial approach could prove useful in treating breast cancer.
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, South Korea.
authors.forename: So-Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, South Korea.
authors.forename: Min-Jin
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, South Korea.
authors.forename: Sang-A
authors.initials: SA
authors.lastname: Park
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, South Korea.
authors.forename: Jung-Shin
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Pharmaceutical Examination Division, Korean Intellectual Property Office, Daejeon, South Korea.
authors.forename: Kyung-Nan
authors.initials: KN
authors.lastname: Min
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, South Korea.
authors.forename: Dae-Kee
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Surgery, School of Medicine, Ewha Womans University, Mokdong Hospital, Seoul, South Korea.
authors.forename: Woosung
authors.initials: W
authors.lastname: Lim
authors.affiliation: Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.|Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, South Korea.
authors.forename: Jeong-Seok
authors.initials: JS
authors.lastname: Nam
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, South Korea.
authors.forename: Yhun Yhong
authors.initials: YY
authors.lastname: Sheen
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured; D014945:Wound Healing; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D017239:Paclitaxel
keywords: Snail; epithelial-to-mesenchymal transition (EMT); metastasis; paclitaxel; transforming growth factor-β (TGF-β)