Benz C C, O'Hagan R C, Richter B, Scott G K, Chang C H, Xiong X, Chew K, Ljung B M, Edgerton S, Thor A, Hassell J A
Cancer Research Institute and Department of Medicine, University of California, San Francisco 94143, USA.
Oncogene. 1997 Sep 25;15(13):1513-25. 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.
由于基因扩增和转录增强，HER2/Neu在25% - 30%的人类乳腺癌中过表达。HER2/neu的转录上调导致每个基因拷贝的mRNA丰度增加6 - 8倍，这可能是由于作用于HER2/neu启动子的转录因子活性升高所致。在此我们报告，在93%的HER2/Neu过表达的人类乳腺肿瘤样本中，参与肿瘤发生的ETS转录因子PEA3的转录本增加。为揭示HER2/Neu阳性乳腺肿瘤中PEA3转录本升高的分子基础而进行的分析表明，HER2/Neu受体酪氨酸激酶启动了细胞内信号级联反应，导致PEA3转录活性增加；转录激活的PEA3通过结合这些基因启动子中的位点来刺激HER2/neu和PEA3基因转录。PEA3还激活编码基质降解蛋白酶的基因转录，这些酶是肿瘤细胞迁移和侵袭所必需的。这些发现表明PEA3参与了HER2/Neu阳性乳腺癌的发生和进展，并提示PEA3和影响其调控的信号蛋白是合适的治疗靶点。
