HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer.
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.
Benz
C C
CC
Cancer Research Institute and Department of Medicine, University of California, San Francisco 94143, USA.
O'Hagan
R C
RC
Richter
B
B
Scott
G K
GK
Chang
C H
CH
Xiong
X
X
Chew
K
K
Ljung
B M
BM
Edgerton
S
S
Thor
A
A
Hassell
J A
JA
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D019556:COS Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; C065788:transcription factor PEA3