DNA Binding Drugs Targeting the Regulatory DNA Binding Site of the ETS Domain Family Transcription Factor Associated with Human Breast Cancer

摘要

Abnormal regulation of gene expression plays an important role in cancer. The first step in the regulation of gene expression requires the binding of transcription factor (TF) to its DNA response element in the gene promoter region. Therefore, interfering with TF-DNA complexes could be a powerful tool for blocking oncogene expression and elucidating how aberrant gene expression contributes to neoplastic phenotypes. The HER2/neu oncogene is amplified and transcriptionally upregulated in 25-30% of human breast cancers. This upregulation has been shown to depend on a highly conserved ETS binding site (EBS) and its upstream AP-2 binding site within the key regulatory region of the HER2/neu promoter. In this study, we investigated a new class of DNA minor groove binding ligands, hairpin pyrrole-imidazole polyamides, as potential TF- DNA inhibitor in gene expression. Several new polyamides were designed specifically targeted to these TF binding sites within HER2/neu promoter region. Polyamides represent a significant advancement in ligand design in that they can achieve a remarkable degree of sequence specificity and high affinity for predetermined DNA sequences. Our results indicate that the first generation of polyamides is potent inhibitors of TF-DNA complex formation and transcription under cell-free conditions.