Metapristone　is　the　most　predominant　biological　active　metabolite　of　mifepristone,　and　being　developed　as　a　novel　cancer　metastasis　chemopreventive　agent　by　us.　Despite　its　prominent　metastasis　chemopreventive　effect,　the　underlying　mechanism　remains　elusive.　Our　study,　for　the　first　time,　demonstrated　that　metapristone　had　the　ability　to　prevent　breast　cancer　cells　from　migration,　invasion,　and　interfere　with　their　adhesion　to　endothelial　cells.　To　explore　the　underlying　mechanism　of　metapristone,　we　employed　the　iTRAQ　technique　to　assess　the　effect　of　metapristone　on　MDA-MB-231　cells.　In　total,　5,145　proteins　were　identified,　of　which,　311　proteins　showed　significant　differences　in　metapristone-treated　cells　compared　to　the　control　group　(P-value　＜0.05).　Bioinformatic　analysis　showed　many　differentially　expressed　proteins　(DEPs)　functionally　associated　with　post-translational　modification,　chaperones,　translation,　transcription,　replication,　signal　transduction,　etc.　Importantly,　many　of　the　DEPs,　such　as　E-cadherin,　vimentin,　TGF-beta　receptor　I/II,　smad2/3,　beta-catenin,　caveolin,　and　dystroglycan　were　associated　with　TGF-beta　and　Wnt　signaling　pathways,　which　were　also　linked　to　epithelial-to-mesenchymal　transition　(EMT)　process.　Further　validation　of　the　epithelial　marker　＂E-caderin＂　and　mesenchymal　marker　＂vimetin＂　were　carried　out　using　immunoblot　and　immunofluorescence.　These　results　have　revealed　a　novel　mechanism　that　metapristone-mediated　metastasis　chemoprevention　is　through　intervening　the　EMT-related　signaling　pathways.