Loss Of Epithelial Androgen Receptor Promotes Castration-resistant Prostate Cancer Metastasis Via TGF-β1 Induced Epithelial–mesenchymal Transition (EMT)

ObjectiveWe previously reported that loss of epithelial AR(probasin-Cre + ARflox/y)in TRAMP prostate may promote tumor progression and cause mice die earlier.The detail mechanisms,however,remain unclear.Therefore,we examined whether castration resistant stem-like prostate cancer cells can increase the epithelial-mesenchymal transition and metastasis.MethodsUsing IHC,Western blot and real-time PCR,we detected the expression of Epithelial–Mesenchymal Transition(EMT)markers.RNA extraction,RT-PCR,and Real-Time RT-PCR,BrdU Incorporation Assay and Establish mice model methods were all used to verify the cell signal of TGF-β1 induced Epithelial–Mesenchymal Transition.Results1.Loss of epithelial AR in pes-ARKO-TRAMP prostate led to higher expression of EMT markers in prostate tumo.2.Loss of AR increase EMT phenotypes in term of cell morphology,detachment,motibility and invasion.3.Decreasing the expression and function of AR in CWR22rv1 cells resulted in fewer anoikis cells.4.AR loss induced EMT transition may be responsible for the early metastasis of the pes-ARKO-TRAMP tumors5.The mechanisms which may involve in the AR loss triggered EMT ConclusionWe found the decrease of the expression of epithelial markers(E-cadherin,Cytokeratin 8 and NKX3.1)and increase of the expression of mesenchymal markers(N-cadherin,Vimentin,and α-SMA)in AR knockout TRAMP primary tumors.Further investigation indicated that AR signal deprivation is associated with cellmorphology transition,high cell mobility,high cell invasion rate and resistance to anoikis in TRAMP prostate tumor cells.Together,these findings implied that knockout AR in TRAMP prostate tumor may lead to epithelial-mesenchymal transition,which may result in earlier metastasis.TGFβ1 and Wnt signaling,as well as AKT and snails,are responsible for EMT change in AR knockout TRAMP tumor cells.In conclusion,ADT therapy induced hormone refractory prostate cancer may gain the ability of metastasis through cell’s EMT which is a phase of poor differentiation.Anti-EMT drugs should be developed to battle the tumor metastasis induced by ADT therapy.The signaling pathways which involved in EMT progress need further elucidation.