INHIBITION OF IRE1α/XBP-1 BRANCH OF UPR BY GSK2850163 DRIVES THE SENSITIVITY TO TAMOXIFEN IN BREAST CANCER CELLS

Abstract

Objective: Tamoxifen is used as the leading treatment against breast cancer and has been broadly applied for the last 40 years. However, resistance development against tamoxifen is one of the major limitations in the effective treatment of breast cancer. The aim of our study was to investigate whether blockage of the IRE1α/XBP-1 branch of UPR by GSK2850163 efficiently limited the carcinogenic ability of tamoxifen-resistant MCF-7 cells. Material and Method: Firstly, tamoxifen-resistant breast cancer cells were obtained by regularly exposing MCF-7 cells to tamoxifen. The biochemical activity of GSK2850163 was confirmed by immunoblotting and qRT-PCR. The possible effect of combined treatment of GSK2850163 and tamoxifen on proliferation, invasion, migration, and colony formation abilities of tamoxifen-resistant breast cancer cells were evaluated by using WST-1 based proliferation assay, Boyden-chamber invasion test, wound-healing assay, and plate colony formation methods, respectively. Result and Discussion: Here, we showed that specific blockage of the IRE1α/XBP-1 by GSK2850163 efficiently limited the carcinogenic ability of tamoxifen-resistant MCF-7 cells. Moreover, co-treatment with tamoxifen and GSK2850163 significantly reduced the invasion, migration, and colony formation abilities of breast cancer cells through improved the anti-carcinogenic property of tamoxifen. Our results strongly suggested that IRE1α/XBP-1 inhibitors may be potent therapeutics in breast cancer treatment.