The Effect And Mechanism Of A New IRE1-XBP1Inhibitor Used In ER+Tamoxifen Resistant Breast Cancer

Objective:More and more studies suggest that the unfolded protein response (UPR) within the endoplasmic reticulum is associated with breast cancer treatment resistance, and there are reports of tamoxifen can causing endoplasmic reticulum stress generated UPR and made downstream xbpis increasing. The aims of the present study were to find the role of the xbp1s in ER-positive tamoxifen resistant breast cancer, and to evaluate a new IRE1-XBP1inhibitor’s effects combined with tamoxifen in endocrine therapy.Methods:(1) Creating a mcf-7tamoxifen-resistant cell lines using low concentration induced method.(2) Using real-time PCR, western blot methods to find changes of xbpis, p-IRE1, IRE1in resistant cell lines compared with normal mcf-7cells.(3) Using RT-PCR method to verify the effects of the new IRE1-XBP1inhibitor.(4)Using MTT method, nude mice experiment, and immunohistochemical method to verify the new IRE1-XBP1inhibitor’s treatment effects combined with tamoxifen, both in vitro and in vivo.Results:(1) The resistant cell lines are1.7-2.4folds less sensitive to tamoxifen and show longer and more branches.(2) Xbp1s mRNA is2.4fold more in resistant cell lines than that in normal cells and with higher p-IRE1、xbp1s proteins. Tamoxifen indeed can enhance the xbp1s mRNA in a short time after added to cells.(3) The new IRE1-XBP1inhibitor can confront the xbp1s’ raising induced by ER stress.(4) The new1RE1-XBP1inhibitor has co-effects with tamoxifen in treating resistant tumor cells both in vitro and in vivo.Conclusion:Tamoxifen can induce ER stress and enhance the IRE1-XBP1pathway and that is maybe one of the reasons why ER-positive breast cancer cells got resistance to tamoxifen after long time use. A new type inhibitor of the IRE1-XBP1 pathway shows co-effects with tamoxifen in treating this kind of resistance and that maybe a potential way of treating ER-positive tamoxifen resistant breast cancer.