Loss of epigenetic regulation disrupts lineage commitment and promotes breast cancer (scATAC-Seq)

Systematically investigating the scores of genes mutated in cancer to discern the real drivers from the inconsequential bystanders is a prerequisite for Precision Medicine but remains challenging. Here, we use CRISPR/Cas9-mediated somatic gene editing in a breast cancer mouse model to assess the transforming potential of 215 recurrent ‘long-tail’ breast cancer genes. Several core and accessory components of the COMPASS-like histone methylase complex, namely KMT2C, KDM6A and ASXL2 cooperated with PIK3CAH1047R mutation to accelerate mammary tumorigenesis in mice and to transform human breast epithelial cells. Mechanistically, mutations of these ‘EpiDrivers’ converged on enhancing the lineage conversion of basal cells to luminal cells prior to tumorigenesis, as well as an aberrant alveolar differentiation program in both luminal and basal cells. Overall, our work suggests that lactation mimicry is associated with the earliest steps of breast cancer. mRNA profiles of mouse mammary tumors modified by either CRISPR-Cas9 (sample 1-19) or conventional Cre-Lox knockout (20-25) with at least 2 tumors per treatment. Controls for each experient are are sgNT (non-targetting) or Kdm6a wildtype respectively.