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

• Published in: Oncogene Vol. 15; no. 13; pp. 1513 - 1525
• Main Authors: BENZ, C. C, O'HAGAN, R. C, HASSELL, J. A, RICHTER, B, SCOTT, G. K, CHANG, C.-H, XIONG, X, CHEW, K, LJUNG, B.-M, EDGERTON, S, THOR, A
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 25.09.1997; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Breast cancer; Breast Neoplasms - metabolism; Cell migration; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; COS Cells; ErbB-2 protein; ETS protein; Fundamental and applied biological sciences. Psychology; Gene amplification; Humans; Intracellular signalling; Kinases; Molecular and cellular biology; Pea3 gene; Promoter Regions, Genetic; Protein-tyrosine kinase receptors; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Therapeutic targets; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Transfection; Tumorigenesis; Tumors; Up-Regulation; Human; Mammary gland diseases; Regulation(control); C-Onc gene; Tumor progression; Gene overexpression; Tumor; Mammary gland; Gene expression; Biological receptor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1201331

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.