The development of novel targeted therapies is urgently required for improving the outcome of breast cancer patients. Chemotherapy is the common treatment option for malignant breast cancer. However, resistance and toxicity 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. Using an unbiased high-throughput screen, we identified 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. Our findings demonstrated that SCUBE3 promotes breast cancer cells' 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. Using interaction studies, we demonstrated that EGFR is a true receptor of SCUBE3 as EGFR and SCUBE3 interact and this interaction mediated progrowth signaling of SCUBE3. These findings underline the importance of SCUBE3 as a potent therapeutic target for treating breast cancer patients.

Citation Format: Benjamin C. Onyeagucha, Kashish Dhillon, Subapriya Rajamanickam, Subbarayalu Panneerdoss, Vijay K. Eedunuuri, Tabrez A. Mohammad, Santosh Timilsina, Yidong Chen, Manjeet K. Rao. SCUBE3 inhibition improves doxorubicin response in breast cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B066.