HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer Academic Article uri icon

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abstract

  • HER2/Neu is overexpressed in 25-30% of all human breast cancers as a result of both gene amplification and enhanced transcription. Transcriptional upregulation of HER2/neu leads to a 6-8-fold increased abundance of its mRNA per gene copy and likely results from the elevated activity of transcription factors acting on the HER2/neu promoter. Here we report that transcripts of PEA3, an ETS transcription factor implicated in oncogenesis, were increased in 93% of HER2/Neu-overexpressing human breast tumor samples. Analyses to uncover the molecular basis for elevated PEA3 transcripts in HER2/Neu-positive breast tumors revealed that the HER2/Neu receptor tyrosine kinase initiated an intracellular signaling cascade resulting in increased PEA3 transcriptional activity; transcriptionally-activated PEA3 stimulated HER2/neu and PEA3 gene transcription by binding to sites in the promoters of these genes. PEA3 also activates transcription of genes encoding matrix-degrading proteinases, enzymes required for tumor cell migration and invasion. These findings implicate PEA3 in the initiation and progression of HER2/Neu positive breast cancer, and suggest that PEA3 and signaling proteins affecting its regulation are appropriate therapeutic targets.

authors

  • Benz, Christopher C
  • O'Hagan, Ronan C
  • Richter, Birgit
  • Scott, Gary K
  • Chang, Chuan-Hsiung
  • Xiong, Xiaohui
  • Chew, Karen
  • Ljung, Britt-Marie
  • Edgerton, Susan
  • Thor, Ann
  • Hassell, John Algernon

publication date

  • September 1997