EN1 Is a Transcriptional Dependency in Triple-Negative Breast Cancer Associated with Brain Metastasis

Cancer Res. 2019 Aug 15;79(16):4173-4183. doi: 10.1158/0008-5472.CAN-18-3264. Epub 2019 Jun 25.


To define transcriptional dependencies of triple-negative breast cancer (TNBC), we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that EN1 (engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance as direct EN1 transcriptional targets. Quantitative proteomic analyses of EN1-bound chromatin complexes revealed association with transcriptional repressors and coactivators including TLE3, TRIM24, TRIM28, and TRIM33. High expression of EN1 correlated with short overall survival and increased risk of developing brain metastases in patients with TNBC. Thus, EN1 is a prognostic marker and a potential therapeutic target in TNBC. SIGNIFICANCE: These findings show that the EN1 transcription factor regulates neurogenesis-related genes and is associated with brain metastasis in triple-negative breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Brain Neoplasms / genetics
  • Brain Neoplasms / mortality
  • Brain Neoplasms / secondary*
  • Co-Repressor Proteins / genetics
  • Co-Repressor Proteins / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics*
  • Humans
  • MCF-7 Cells
  • Prognosis
  • Transcription Factors / genetics
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / mortality*
  • Triple Negative Breast Neoplasms / pathology*
  • Xenograft Model Antitumor Assays


  • Co-Repressor Proteins
  • EN1 protein, human
  • Homeodomain Proteins
  • TLE3 protein, human
  • Transcription Factors