Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer

Cell Rep. 2017 Mar 7;18(10):2359-2372. doi: 10.1016/j.celrep.2017.02.025.


While the multiple endocrine neoplasia type 1 (MEN1) gene functions as a tumor suppressor in a variety of cancer types, we explored its oncogenic role in breast tumorigenesis. The MEN1 gene product menin is involved in H3K4 trimethylation and co-activates transcription. We integrated ChIP-seq and RNA-seq data to identify menin target genes. Our analysis revealed that menin-dependent target gene promoters display looping to distal enhancers that are bound by menin, FOXA1 and GATA3. In this fashion, MEN1 co-regulates a proliferative breast cancer-specific gene expression program in ER+ cells. In primary mammary cells, MEN1 exerts an anti-proliferative function by regulating a distinct expression signature. Our findings clarify the cell-type-specific functions of MEN1 and inform the development of menin-directed treatments for breast cancer.

Keywords: MEN1; breast cancer; enhancer; epigenetics; histone H3K4 trimethylation; menin; oncogene; transcription; tumor suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Enhancer Elements, Genetic / genetics*
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / metabolism
  • Female
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Regulation, Neoplastic
  • Genomics
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Histones / metabolism
  • Humans
  • Lysine / metabolism
  • Methylation
  • Oncogenes*
  • Promoter Regions, Genetic
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins / genetics*
  • Transcription, Genetic


  • Estrogen Receptor alpha
  • FOXA1 protein, human
  • GATA3 Transcription Factor
  • Hepatocyte Nuclear Factor 3-alpha
  • Histones
  • MEN1 protein, human
  • Proto-Oncogene Proteins
  • Estradiol
  • Lysine