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Multiple drug resistance (MDR) is main cause of chemotherapy failure in breast cancer. Herein, we tried to find the mechanism of MDR. Since overexpression of glucosylceramide synthase (GCS) plays an important role in development of MDR, we analyzed expression levels of many molecules from TCGA data to find a connection between GCS and other molecules. Interestingly, correlations between GCS and ceramide synthase 6 (CerS6), and between glucocerebosidase (GBA) and CerS2, 4, 5 were analyzed. To further analyze whether these correlations are true, we treated C16~C24-ceramide to MD-MBA-361 cells. C24-ceramide treatment for 48 and 72 hrs increased GBA expression, which increased susceptibility of apoptosis upon doxorubicin treatment. Moreover, C16-ceramide treatment for 16 weeks increased GCS expression, which also induced MDR1 protein expression. Recently we found that bortezomib, an FDA-approved proteasome inhibitor, increased CerS2 and decreased CerS6 expressions in a dose-dependent manner. To further understand whether bortezomib affects MDR, bortezomib was treated with doxorubicin for 6-8 months and it prevented doxorubicin-induced MDR development by reducing CerS6 and elevating CerS2. In conclusion, downregulation of CerS6 and upregulation of CerS2 is a good strategy to prevent development of MDR, and bortezomib can be used for the prevention of acquired MDR. Citation Format: Kim Shin, Kim Dongeun, Park Inkeun, Park Woo-Jae. Long-term treatment of bortezomib reduced resistance to doxorubicin by reducing CerS6/GCS and elevating CerS2/GBA expressions [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A47.