A novel HER2 gene body enhancer contributes to HER2 expression

Oncogene. 2018 Feb 1;37(5):687-694. doi: 10.1038/onc.2017.382. Epub 2017 Oct 16.


The transcriptional regulation of the human epidermal growth factor receptor-2 (HER2) contributes to an enhanced HER2 expression in HER2-positive breast cancers with HER2 gene amplification and HER2-low or HER2-negative breast cancers following radiotherapy or endocrine therapy, and this drives tumorigenesis and the resistance to therapy. Epigenetic mechanisms are critical for transcription regulation, however, such mechanisms in the transcription regulation of HER2 are limited to the involvement of tri-methylated histone 3 lysine 4 (H3K4me3) and acetylated histone 3 lysine 9 (H3K9ac) at the HER2 promoter region. Here, we report the identification of a novel enhancer in the HER2 3' gene body, which we have termed HER2 gene body enhancer (HGE). The HGE starts from the 3' end of intron 19 and extends into intron 22, possesses enhancer histone modification marks in specific cells and enhances the transcriptional activity of the HER2 promoters. We also found that TFAP2C, a known regulator of HER2, binds to HGE and is required for its enhancer function and that DNA methylation in the HGE region inhibits the histone modifications characterizing enhancer and is inversely correlated with HER2 expression in breast cancer samples. The identification of this novel enhancer sheds a light on the roles of epigenetic mechanisms in HER2 transcription, in both HER2-positive breast cancer samples and individuals with HER2-low or HER2-negative breast cancers undergoing radiotherapy or endocrine therapy.

Publication types

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

MeSH terms

  • Breast / pathology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • DNA Methylation / genetics
  • Enhancer Elements, Genetic / genetics*
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Histones / genetics
  • Humans
  • Introns / genetics
  • Promoter Regions, Genetic / genetics
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / metabolism
  • Transcription Factor AP-2 / genetics
  • Transcription Factor AP-2 / metabolism*


  • Histones
  • TFAP2C protein, human
  • Transcription Factor AP-2
  • ERBB2 protein, human
  • Receptor, ErbB-2