Aim:Estrogen receptor-α(ER-α)activation drives the progression of luminal breast cancers.Signaling by transforming growth factor-β(TGF-β)typically opposes the actions of ER-α;it also induces epithelial-mesenchyma...Aim:Estrogen receptor-α(ER-α)activation drives the progression of luminal breast cancers.Signaling by transforming growth factor-β(TGF-β)typically opposes the actions of ER-α;it also induces epithelial-mesenchymal transition(EMT)programs that promote breast cancer dissemination,stemness and chemoresistance.The impact of EMT programs on nongenomic ER-αsignaling remains unknown and was studied herein.Methods:MCF-7 and BT474 cells were stimulated with TGF-βto induce EMT programs,at which point ER-αexpression,localization,and nongenomic interactions with receptor tyrosine kinases and MAP kinases(MAPKs)were determined.Cell sensitivity to anti-estrogens both before and after traversing the EMT program was also investigated.Results:TGF-β-stimulated MCF-7 and BT474 cells to acquire EMT phenotypes,which enhanced cytoplasmic accumulation of ER-αwithout altering its expression.Post-EMT cells exhibited:(1)elevated expression of EGFR and IGF1R,which together with Src formed cytoplasmic complexes with ER-α;(2)enhanced coupling of EGF,IGF-1 and estrogen to the activation of MAPKs;and(3)reduced sensitivity to tamoxifen,an event reversed by administration of small molecule inhibitors against the receptors for TGF-β,EGF,and IGF-1,as well as those against MAPKs.Conclusion:EMT stimulated by TGF-βpromotes anti-estrogen resistance by activating EGFR-,IGF1R-,and MAPK-dependent nongenomic ER-αsignaling.展开更多
基金Research support was provided in part by the National Institutes of Health to W.P.S.(CA129359,CA177069,and CA194518).
文摘Aim:Estrogen receptor-α(ER-α)activation drives the progression of luminal breast cancers.Signaling by transforming growth factor-β(TGF-β)typically opposes the actions of ER-α;it also induces epithelial-mesenchymal transition(EMT)programs that promote breast cancer dissemination,stemness and chemoresistance.The impact of EMT programs on nongenomic ER-αsignaling remains unknown and was studied herein.Methods:MCF-7 and BT474 cells were stimulated with TGF-βto induce EMT programs,at which point ER-αexpression,localization,and nongenomic interactions with receptor tyrosine kinases and MAP kinases(MAPKs)were determined.Cell sensitivity to anti-estrogens both before and after traversing the EMT program was also investigated.Results:TGF-β-stimulated MCF-7 and BT474 cells to acquire EMT phenotypes,which enhanced cytoplasmic accumulation of ER-αwithout altering its expression.Post-EMT cells exhibited:(1)elevated expression of EGFR and IGF1R,which together with Src formed cytoplasmic complexes with ER-α;(2)enhanced coupling of EGF,IGF-1 and estrogen to the activation of MAPKs;and(3)reduced sensitivity to tamoxifen,an event reversed by administration of small molecule inhibitors against the receptors for TGF-β,EGF,and IGF-1,as well as those against MAPKs.Conclusion:EMT stimulated by TGF-βpromotes anti-estrogen resistance by activating EGFR-,IGF1R-,and MAPK-dependent nongenomic ER-αsignaling.
