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RUNX1  encodes a RUNX family transcription factor (TF) and was recently identified as a novel mutated gene in human luminal breast cancers. We found that  Runx1  is expressed in all subpopulations of murine mammary epithelial cells (MECs) except the secretory alveolar luminal cells. Conditional knockout of  Runx1  in MECs by  MMTV-Cre  led to a decrease in luminal MECs, largely due to a profound reduction in the estrogen receptor (ER)-positive mature luminal subpopulation, a phenotype that could be rescued by the loss of either  Trp53  or  Rb1 . Mechanistically RUNX1 represses  Elf5 , a master regulatory TF gene for alveolar cells, and regulates mature luminal TF/co-factor genes (e.g.,  Foxa1  and  Cited1 ) involved in the ER program. Collectively, our data identified a key regulator of the ER +  luminal lineage whose disruption may contribute to the development of ER +  luminal breast cancer when under the background of either  TP53  or  RB1  loss.

RUNX1, a transcription factor mutated in breast cancer, controls the fate of ER-positive mammary luminal cells