Loss of epigenetic regulation disrupts lineage integrity, inducesaberrant alveogenesis and promotes breast cancer.
Langille E. et al.
Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for Precision Medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent 'long-tail' breast cancer genes, which revealed epigenetic regulation as a major tumor suppressive mechanism. We report that components of the BAP1 and the COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1 and ASXL1/2 ("EpiDrivers"), cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of PIK3CAH1047R and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDrivers mutations are found in ~39\% of human breast cancers and ~50\% of ductal-carcinoma-in-situ express casein suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology.