Technologies such as sequencing, epigenetic, proteomic or metabolomic profiling have resulted in large sets of data. Functional annotation of the genome is a key challenge for a fundamental understanding of disease. We combined genetic model organisms and repairable mutagenesis with in vivo mouse genetics and human cohort studies to functionally characterize candidate breast cancer genes. Using mouse genetics, we showed that RANKL and its receptor RANK are critical regulators of sex hormone and BRCA1mutation-driven breast cancer providing a rationale for breast cancer prevention trials in BRCA1 carriers using RANKL blockade. We also showed that serum levels of RANKL are potentially indicative of predisposition and progression of breast cancer in humans. The ground work we have laid in this innovator award is now being translated into a clinical trial with the goal to prevent breast cancer, starting in November 2018. During the course of our work we realized that RANK links female sex hormones to lung cancer and gender bias in lung cancer. We also performed a near-genome wide screen in Drosophila for genes that control tumor progression, allowing us to identify multiple novel tumor suppressor genes. Finally, we have now generated more than 100000 murine haploid ES cell clones targeting approximately 16500 different genes. We also developed new methods to generate blood vessels from haploid ES cells which allows us to genetically explore novel factors for tumor angiogenesis. One of these factors, Apelin, indeed cooperates with VEGFR signaling and, in mutant mouse models, appears to be a key regulator of tumor neo-angiogenesis and survival in breast cancer. Thus, we have successfully initiated all proposed aims with the vision to identify and functionally annotate breast cancer genes. Importantly, the innovator award allowed us to lay the ground work on RANKL/RANK which is now directly being translated into a clinical trial with the goal to prevent breast cancer.