Specific Inhibition of HER-2/NEU Transcription Initiation
Abstract
A polypurine tract (PPT) containing multiple GGA repeats in the HER-2/neu promoter is important to control HER-2/neu transcription. We investigated the ability of the PPT to form a G-quadruplex-related secondary structure using biochemical techniques and screened a small family of potential G-quadruplex ligands that could stabilize PPT secondary structure formation in solution. Telomestatin and a lead compound in the fluoroquinolone class stabilize the HER- 2/neu PPT secondary structure in solution and reduce HER-2/neu expression in breast cancer cells. We conclude the HER-2/neu promoter can form a stable secondary structure known as a tetrad:heptad in solution. Further studies are needed to fully characterize the secondary structure and link the effects of compounds on HER-2/neu expression to their direct interaction with the HER-2/neu promoter using reporter cell lines that are currently under construction. We also identified a second potential therapeutic target in the HIF-1 alpha gene promoter capable of forming a G-quadruplex structure that can also bind to G-quadruplex ligands and serve as a basis of developing small molecule inhibitors of gene transcription for the treatment of breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2007
- Accession Number
- ADA486610
Entities
People
- Scot W. Ebbinghaus
Organizations
- University of Arizona