title: Inhibition of breast cancer metastases by a novel inhibitor of TGFβ receptor 1.
abstract: BACKGROUND
  Transforming growth factor beta (TGFβ), which is implicated in metastasis to various organs in breast cancer, is a potential target for new antitumor metastasis drugs.
  
  
  METHODS
  To identify specific inhibitors of TGFβ receptor 1 (TGFβR1) in breast cancer metastasis, a virtual library of more than 400000 different compounds was screened by molecular docking modeling and confirmed with Smad-binding element luciferase and TGFβR1 kinase assays. Affymetrix GeneChip expression analysis of mRNA levels and real-time polymerase chain reaction were performed to determine expression changes of TGFβ-mediated, metastasis-associated genes in breast cancer cells after treatment with the small-molecule inhibitor YR-290. YR-290 was also examined for its effects on breast cancer migration, invasion, and metastasis using transwell and epithelial-to-mesenchymal transition (EMT) assays in vitro and three different mouse (BALB/c and NU/NU nude) models (n = 10 per group). Kaplan-Meier analyses were used to assess survival. All statistical tests were two-sided.
  
  
  RESULTS
  YR-290 interacted with the kinase domain of TGFβR1, abrogated kinase activity (half maximal inhibitory concentration = 137nM, 95% confidence interval = 126.4 to 147.6nM) and inhibited the TGFβ-mediated downstream signaling pathway and metastasis-associated genes in breast cancer cells. YR-290 inhibited TGFβ-modulated breast cancer cell migration and invasion. In tumor metastasis mouse models, YR-290 almost completely blocked cancer metastasis. Numbers of lung tumor nodules of mice treated with 1mg/kg and 5mg/kg YR-290 were reduced by 74.93% (95% confidence interval = 61.45% to 88.41%) and 94.93% (95% confidence interval = 82.13% to 100%), respectively, compared with control mice. Treatment with YR-290 also statistically significantly prolonged the survival of tumor-bearing mice.
  
  
  CONCLUSIONS
  YR-290 is a novel inhibitor of tumor metastasis that works by blocking TGFβ signaling pathways.
authors.affiliation: Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Rd, Shanghai, China.
authors.forename: Yuanzhang
authors.initials: Y
authors.lastname: Fang
authors.forename: Yihua
authors.initials: Y
authors.lastname: Chen
authors.forename: Linxi
authors.initials: L
authors.lastname: Yu
authors.forename: Cong
authors.initials: C
authors.lastname: Zheng
authors.forename: Ya
authors.initials: Y
authors.lastname: Qi
authors.forename: Zhenxi
authors.initials: Z
authors.lastname: Li
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Yang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tieliu
authors.initials: T
authors.lastname: Shi
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D000230:Adenocarcinoma / Q000517:prevention & control* / Q000556:secondary*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002243:Carbolines / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; C578382:N-phenylacetyl-1,3,4,9-tetrahydro-1H-beta-carboline; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I