Chromosome instability is highly prevalent in cancer and drives large scale chromosomal imbalances, known as aneuploidies. However, how aneuploidy contributes to tumorigenesis remains difficult to study due to the vast numbers of genes affected. Here, we develop a CRISPR-Knock Out and Activation Linked Assay (CRISPR-KOALA), enabling high-throughput bidirectional genetic screens in immune-competent mouse models of cancer. We developed a compendium of the ten most frequently altered human chromosome arms in basal-like breast cancer (BLBC), a copy number-driven disease. Using CRISPR-KOALA we screened the mouse orthologs of all 3,752 genes on these arms and identified 90 cancer driver genes, the vast majority of which have hitherto unknown functions in cancer. These genes drive distinct signalling pathways including MAPK, Hippo and WNT, reflecting the high degree of BLBC heterogeneity. Manipulating the identified cancer driver genes overcomes the need for copy number alterations (CNAs) in p53-mutant BLBC mouse models. Mechanistically, we uncover PLGRKT as a potent oncogene that lies adjacent to the immune checkpoint gene CD274/PD-L1 on chr9p and show that its tumor-promoting activity is associated with the creation of highly stress-resistant mitochondria that promote tumor cell survival. Thus, our findings reveal that arm-level CNAs can function to select specific driver genes to promote heterogenous biological processes.