SCUBE3 Inhibition Combined with Doxorubicin Improves Mouse Orthotopic Breast Cancer Model
Onyeagucha Benjamin1,2,4, Panneerdoss Subbarayalu1,2, Rajamanickam Subapriya1,2, Eedunuri Vijay1,2. Mohammad Tabrez Anwar1,3, Chen Yidong1, 3, Rao Manjeet1,2
1Greehey Children's Cancer Research Institute
2Department of Cell Systems and Anatomy
3Department of Epidemiology and Statistics, The University of Texas Health Science center at San Antonio, Texas, 78229 USA
4Department of Sciences and Mathematics, The Mississippi University for Women, MS 39701
The development of novel targeted therapies is urgently required for improving the treatment outcome of breast cancer patients. Chemotherapy is a 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 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. Silencing of SCUBE3 expression acts as a potent suppressor of cell viability, tumor cells growth and improves doxorubicin outcome in a pre-clinical mouse model. Interestingly, we observed a dose-dependent nuclear translocation of SCUBE3 protein in doxorubicin treated-cells suggesting that nuclear localization of SCUBE3 may be important for SCUBE3 protection effects against doxorubicin treatment. Furthermore, our results demonstrated that SCUBE3 mediates its pro-tumor effects by regulating genes involved in growth and survival in the MAP-Kinase pathway, DNA damage repair 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 pro-growth signaling of SCUBE3. These findings highlight the importance of SCUBE3 as a potent therapeutic target for treating and predicting treatment outcomes in breast cancer patients.