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. We evaluated several potential lead compounds for their ability to suppress HER-2/neu expression in breast cancer cells. Circular dichroism studies with the distal half of the PPT were similar to findings previously reported for tetrad:heptad DNA. DNA polymerase arrest assays demonstrated potassium induced arrest, and several G-quadruplex interactive compounds that stabilize the HER-2/neu PPT secondary structure were identified from this assay. 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. Compounds that stabilize the tetrad:heptad were identified and some of them reduced HER-2/neu expression in breast cancer cells. 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2005
- Accession Number
- ADA439256
Entities
People
- Scot W. Ebbinghaus
Organizations
- University of Arizona