title: RUNX1, a transcription factor mutated in breast cancer, controls the fate of ER-positive mammary luminal cells.
abstract: 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.
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Boston, United States.
authors.forename: Maaike P A
authors.initials: MP
authors.lastname: van Bragt
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Boston, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Boston, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Boston, United States.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C102208:Cited1 protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C500759:Elf5 protein, mouse; C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D016160:Retinoblastoma Protein; C493726:Runx1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C045073:Cre recombinase; D019426:Integrases
keywords: ELF5; RUNX1; cell fate; developmental biology; estrogen receptor; human; human biology; luminal breast cancer; master regulatory transcription factor; medicine; mouse; stem cells