Genetic Interaction Screen for Breast Cancer Progression Driver Genes.

摘要

The overall goal of the project is to identify driver mutations/genes that promote breast cancer progression. We have screened 70 genes, which are mutated in human breast cancer at low frequencies, by examining whether their piggyBac insertional mutants could promote the growth and metastasis of the MMTV-PyVT breast tumors in mice. We have discovered that 15 of them alter the onset of breast tumor formation while four exacerbate tumor metastasis. Among them, Trim33 and Ahrr have been recently reported as tumor suppressors, demonstrating the effectiveness of our screen. We have further confirmed that the Grik3 gene/mutation identified in the screen promotes breast cancer development by changing the onset and growth of the tumors. Our mechanistic studies have shown that Grik3 regulates the cell cycle, but not apoptosis, by inducing the expression of p53 and p21. In a complementary study, we have examined the role of tumor heterogeneity in contributing to TNBC invasion/metastasis. By co-culturing different breast cancer cells that are tagged with fluorescent proteins, we have discovered that breast cells of different genotypes could promote invasion/metastasis behavior of other cells in a cell line-specific manner. Our study establishes a new paradigm for studying the contribution of tumor heterogeneity to breast cancer biology.