Breast cancer remains a significant health concern worldwide. Integrative genomic analysis of clinical breast cancer samples identified Metadherin (MTDH) as a driver gene that promotes breast cancer initiation, progression, and treatment resistance. Using genetically engineered mouse models, we found that MTDH sustains breast cancer progression and metastasis via interacting with SND1, and acute Mtdh loss inhibits breast cancer development. Using a structure-based small-molecule screen, we obtained a serial of MTDH/SND1 inhibitors. Treatments of the compounds suppress breast tumor growth and metastasis and sensitize breast cancer to chemotherapy by sensitizing cancer cells to stress-induced apoptosis. This series of studies illustrates the use of mouse models to validate clinically relevant novel therapeutic targets for breast cancer and illustrates the functional mechanism of driver genes in cancer progression and metastasis.

Citation Format: Yibin Kang. Identification, validation, and therapeutic targeting of a driver gene in poor-prognosis breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA13.