Abstract 5892: SCUBE3 promotes therapy resistance in triple negative breast cancer

Abstract Introduction: The development of novel targeted therapies is urgently required for improving the outcome of triple negative breast cancer (TNBC) patients. Chemotherapy is the common treatment option for TNBC. However, resistance and tumor relapse remain the major obstacles hindering the effectiveness of chemotherapeutic agents in cancer patients. Therefore, identifying genes/factors that sensitize breast cancer cells to chemotherapeutic agents could improve treatment outcome in patients. Here we report Signal peptide CUB domain EGF-like 3 (SCUBE3) genes as a novel therapeutic adjuvant that can improve the efficacy of doxorubicin, a chemotherapeutic agent commonly used in treating breast cancer patients. Methods: Unbiased high-throughput loss of function genomic screen was performed on breast cancer cells in the presence or absence of doxorubicin. Breast cancer cells lines (MDA-MB-231 and MDA-MB-468) were purchased from the American Type Culture Collection and cultured in standard medium. Breast cancer cells were transfected either with SCUBE3 overexpression plasmid or shRNA specific to SCUBE3. These overexpression/knockdown breast cancer cells were analyzed for cell viability, migration, invasion, colony formation, cell cycle, apoptosis assays, western blotting, and in vivo tumor xenograft study. Results: Our finding demonstrated that SCUBE3 promotes breast cancer cell progression as knockdown of SCUBE3 inhibited the ability of breast cancer cells to form colony, migrate, and invade, while overexpression of SCUBE3 promoted tumor growth in preclinical mouse models. Our results revealed that SCUBE3 mediates its protumor effects by regulating genes involved in growth and survival in the MAPK pathway, DNA damage surveillance pathway including RAD51 and FOXM1, and apoptotic pathway including Mcl-1. We demonstrated that SCUBE3 promotes tumor growth and progression by interacting with and activating several oncoproteins. Conclusions: Overall, our data suggests that SCUBE3 can be a potent therapeutic target for treating TNBC patients. Citation Format: Deepika Singh, Daisy Medina, Benjamin Onyeagucha, Rahul Mojidra, Panneerdoss Subbarayallu, Alex Taylor, Dongwen Lyu, Santosh Timilsina, Prabhakar Pitta Venkata, Saif S R Nirzhor, Shahad M. Abdulsahib, Trong Phat Do, Yidong Chen, Ratna Vadlamudi, Manjeet K. Rao. SCUBE3 promotes therapy resistance in triple negative breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5892.