Breast Cancer Risk Enhancers Breast cancer (BCa) genetic risk is partly explained by rare pathological mutations (BRCA1 and BRCA2, for example) and >70 common variants that contribute to risk; the latter as revealed by genome-wide association (GWAS) hits. The major 'problem' of GWAS loci is the lack of mechanistic understanding of how such risk alleles function and how they contribute to genetic risk. This is further exacerbated by the fact that the vast majority (>90% of BCa risk alleles) resides in non-coding DNA such as enhancers. This application intends to systematically elucidate mechanisms of action and target genes of 20 newly identified BCa risk enhancers. This will be achieved by measuring allele-specific enhancer activity (Aim #1), allele-specific nucleosome depletion and transcription factor occupancy (Aim #2), identifying risk enhancer target genes, using eQTL, 3C and CRIPR/Cas (Aim #3) and finally by determining the functionality of risk genes in terms of cancer phenotypes (Aim #4). The results will link functionality of variants with breast biology and elucidate previously unanticipated risk mechanisms. The results will have a major impact on many aspects of disease including population based screening for early disease detection, and new treatments.