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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

155 Scopus citations

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.

Original languageEnglish
Pages (from-to)1513-1525
Number of pages13
JournalOncogene
Volume15
Issue number13
DOIs
StatePublished - 1997

Keywords

  • Breast cancer
  • Ets transcription factor
  • HER2/Neu
  • PEA3

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