Inhibition of Breast Cancer Metastases by a Novel Inhibitor of TGFβ Receptor 1
Menée in vitro et sur trois modèles murins, cette étude met en évidence un mécanisme par lequel un composé appelé YR-20, en bloquant les voies de signalisation de TGFβ, inhibe le processus métastatique d'un cancer du sein
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.