title: Teriflunomide, an immunomodulatory drug, exerts anticancer activity in triple negative breast cancer cells.
abstract: Triple-negative breast cancer (TNBC) is defined as a group of primary breast cancers lacking expression of estrogen, progesterone, and human epidermal growth factor receptor-2 (HER-2) receptors, characterized by higher relapse rate and lower survival compared with other subtypes. Due to lack of identified targets and molecular heterogeneity, conventional chemotherapy is the only available option for treatment of TNBC, but non-discordant positive therapeutic efficacy could not be achieved. Here, we demonstrated that these TNBC cells were sensitive to teriflunomide, which was a well-known immunomodulatory drug for treatment of relapsing multiple sclerosis (MS). Potent anti-cancer effects in TNBC in vitro, including proliferation inhibition, cell cycle delay, cell apoptosis, and suppression of cell motility and invasiveness, could be achieved with this agent. Of note, we showed that multiple signals involved in TNBC proliferation, survival, migratory, and invasive potential were under regulation by teriflunomide. Among them, we identified down-regulation of growth factor receptors to abolish growth maintenance, suppression of c-Myc, and cyclin D1 to contribute to its anti-proliferative effect, modulation of components of cell cycle to induce S-phase arrest, degradation of Bcl-xL, and up-regulation of BAX via activation of MAPK pathway to induce apoptosis, and inhibition of epithelial-mesenchymal transition (EMT) process, matrix metalloproteinase-9 (MMP9) expression, and inactivation of Src/FAK to reduce TNBC migration and invasion. The results identified teriflunomide may be of therapeutic benefit for the more aggressive and difficult-to-treat breast cancer subtype, indicating the use of teriflunomide for clinical trials for treatment of TNBC patients.
authors.affiliation: Comprehensive Breast Health Centre, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Ou
authors.initials: O
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, Xiangcheng People's Hospital, Suzhou, 215131, China.
authors.forename: Weili
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Qiaoming
authors.initials: Q
authors.lastname: Zhi
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Xue
authors.affiliation: Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hongchun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Xiangcheng People's Hospital, Suzhou, 215131, China.
authors.forename: Daoming
authors.initials: D
authors.lastname: Shen
authors.affiliation: Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zuoquan
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China jiangmin1023@126.com zuoquan_xie@163.com.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003437:Crotonates / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates; D007155:Immunologic Factors / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D009570:Nitriles; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014052:Toluidines / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology
chemical_list: D000970:Antineoplastic Agents; D003437:Crotonates; D006885:Hydroxybutyrates; D007155:Immunologic Factors; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Src; Triple negative breast cancer; cell cycle; epithelial-mesenchymal transition; growth factor receptor; teriflunomide