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

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. DOI: http://dx.doi.org/10.7554/eLife.03881.001
eLife digest Stem cells can develop into the many types of specialized cell found in the body. Several proteins regulate these transformations by switching on and off the expression of genes that are specific to different cell types. Disrupting these proteins can cause the development of cells to go awry and can lead to cancer. A protein called RUNX1 controls gene expression to direct the development of blood cells. Mutations in the gene encoding this protein have been linked to blood cancers and a particular type of breast cancer, which begins in the cells that line the ducts that carry milk towards the nipple. Mammary duct-lining cells develop from a pool of stem cells that produces breast tissue cells. Now van Bragt et al. have found that RUNX1 is expressed in the cells lining the ducts of the mammary glands, except those that produce milk. Deleting the gene for RUNX1 in mice reduced the number of duct-lining cells, especially a subgroup of cells that are the sensors for the hormone estrogen. Through experiments on breast cancer cells, van Bragt et al. found that RUNX1 is able to dictate the fate of duct-lining breast cells by controlling other protein regulators. RUNX1 boosts the activity of at least one regulator that encourages the cells to become duct-lining cells and represses another regulatory protein that turns cells into milk-producing cells. Next, van Bragt et al. found that, in mice lacking the gene for RUNX1, reducing the amounts of certain proteins that normally suppress the formation of tumors restored the populations of estrogen-sensing duct-lining cells. This suggests that mutations in the gene encoding RUNX1, coupled with the loss of a tumor-suppressing protein, may contribute to the development of cancer in the cells that line the breast ducts. The next challenge is to determine exactly how RUNX1 mutations work together with the loss of the tumor-suppressing protein to drive breast cancer development. This knowledge may translate into new approaches to prevent or treat this type of breast cancer. DOI: http://dx.doi.org/10.7554/eLife.03881.002