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

Koen M A Dreijerink, Anna C Groner, Erica S M Vos, Alba Font-Tello, Lei Gu, David Chi, Jaime Reyes, Jennifer Cook, Elgene Lim, Charles Y Lin, Wouter de Laat, Prakash K Rao, Henry W Long, Myles Brown

Research output: Contribution to journalArticleAcademicpeer-review

46 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2359-2372
Number of pages14
JournalCell Reports
Volume18
Issue number10
DOIs
Publication statusPublished - 7 Mar 2017

Keywords

  • Breast Neoplasms/genetics
  • 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

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