Genetic Interaction Screen for Breast Cancer Progression Driver Genes.

摘要

Breast cancer is the most common malignant cancer among American women and the second leading cause of cancer death in women. The analysis of genetic alterations in human breast cancers has revealed that individual tumors accumulate mutations in approximately ninety different genes. However, the significance of most mutations to cancer development remains unknown. The ability to differentiate between driver and bystander mutations will provide valuable insight into how breast cancers develop and how to tailor individualized strategies for the diagnosis and treatment of cancer. We performed a screen to test the roles of seventy breast cancer mutated genes in mouse mammary tumorigenesis using the MMTV-PyVT mouse breast cancer model and piggyBac insertional mutation strains. We found that insertional mutations in 23 genes altered the onset of tumor formation and four genes exacerbated tumor metastasis. Among the 23 genes, Trim33 and Ahrr, have been recently reported as tumor suppressors, demonstrating the effectiveness of our screen. We have further confirmed the oncogenic roles of two metabolism related genes, Grik3 and HadHB with in vitro tumor assays and are currently performing mechanistic studies. The next phase of questions will be focused on how disruption of metabolism contributes to tumor development and progression.