Drug-resistance of chemotherapy is the leading cause of mortality in breast cancer patients. Understanding how drug-resistant cancer cell survival is of great importance for the breast cancer therapy. Here, we identified a key protein, TM9SF4, namely transmembrane 9 superfamily, isoform 4, which play vital role in drug-resistant breast cancer survival. TM9SF4 is significantly up-regulated in Adriamycin(ADM)-resistant breast cancer cells MCF-7/ADM compared to its parental wildtype cell line MCF-7/WT. Knockdown of TM9SF4 using lenti-TM9SF4-shRNA dramatically decreased cell viability and induced cell death of MCF-7/ADM. Moreover, drug-resistant xenografts derived from animal model also showed a significantly reduced growth rate after the delivery of lenti-TM9SF4-shRNA. The underlying mechanism may be related to the triggering of ER stress, leading to unfolded protein response, which will induce apoptosis/necrosis, causing cell death. Our study provides TM9SF4 as a promising target for the overcoming of drug-resistance in clinical breast cancer therapy. Elevated expression of TM9SF4 in drug-resistant MCF-7 cells TM9SF4 is essential for MCF-7/ADM cell survival Effect of TM9SF4 inhibition on the growth of MCF-7/ADM tumor xenografts Effect of TM9SF4 suppression on ER stress in MCF-7/ADM and drug-resistant human xenografts. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.