To unveil the function of the uPE1 or the “Dark proteins”, we are utilizing CRISPR-based genome-wide functional genomics screens, targeting to identify genes and mutations that promote progression of breast cancer, especially the highly aggressive basal-like subtype with TP53 mutations. As a model system, we employ MCF10A cell lines expressing 10 prevalent mutant forms of p53 proteins that have been comprehensively analyzed for cancer-related phenotypes and molecular profiles by RNA-Seq and ChIP-Seq. From in vitro and xenograft-based screens on these cell lines, a few hundred hits, including several uPE1 proteins, have been identified to promote more aggressive behaviors of cells expressing different p53 mutants. We are currently performing individual validation of the hits in parallel with integrated bioinformatics analysis to infer their cellular functions.