Renal　cell　carcinoma　(RCC)　has　the　third　highest　mortality　rate　among　urological　tumors,　and　20-30%　of　RCC　patients　present　with　metastatic　RCC　at　the　time　of　diagnosis.　Although　recent　studies　have　indicated　that　estrogen　receptor　β　(ERβ)　could　play　promoting　roles　in　RCC　progression,　the　detailed　mechanisms　remain　to　be　clarified.　In　the　present　study,　we　found　that　expression　of　ERβ,　but　not　ERα,　increases　with　tumor　stage　and　grade,　and　also　observed　that　modification　of　ERβ　signals　using　estrogens/anti-estrogens,　shRNA　knockdown　of　ERβ　and　overexpression　of　ERβ　using　ectopic　cDNA　affects　RCC　cell　proliferation,　migration　and　invasion.　Mechanism　analysis　revealed　that　ERβ　can　promote　RCC　cell　invasion　via　an　increase　in　transforming　growth　factor　β1　(TGF-β1)/SMAD3　signals,　and　interrupting　TGF-β1/SMAD3　signals　with　a　TGFβR1　inhibitor　can　reverse/block　ERβ-increased　RCC　cell　migration.　Importantly,　preclinical　analyses　using　in vivo　mouse　models　of　RCC　revealed　that　targeting　of　this　newly　identified　ERβ/TGF-β1/SMAD3　pathway　with　either　the　FDA-approved　anti-estrogen　ICI182,780　(Faslodex)　or　a　selective　ERβ　antagonist　4-[2-phenyl-5,7　bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol　can　significantly　reduce　RCC　tumor　growth　and　invasion,　which　may　be　suitable　as　the　basis　for　novel　therapies　to　more　effectively　suppress　metastatic　RCC.