Adenovirus-Mediated p202 Gene Transfer in Breast Cancer Gene Therapy

摘要

The main goal of this project is to study the anti-tumor activity of p2O2 (aim 1), the potential application to breast cancer gene therapy (aim 2) and the anti-tumor activity of IFIX (aim 3). Our studies show that Ad-p202 infection induces growth inhibition and sensitize breast cancer cells to TNF- ALPHA induced apoptosis. In addition, we demonstrate for the first time that Ad- p202 infection induces apoptosis. More impotently, we show the efficacy of Ad- p202 treatment on breast cancer xenograft models. In search for the potential human ortholog of mouse p202, we identified a new human HIN-200 gene, IFIX (WN- Inducible protein X) We found that the expression of IFIX is reduced in breast tumor tissues and breast cancer cell lines and that the enforced expression of IFIX in breast cancer cell lines reduces their growth and tumorigenicity. We also demonstrate the treatment efficacy of an IFIX-based gene therapy in an orthotopic breast cancer model. To investigate the mechanism of the IFIX alpha1- mediated tumor suppression, we found a novel interaction between IFIXalpha1 and HDM2. Importantly, IFIXalpha1 destabilizes HDM2 leading to increased p53 stability and enhanced p53-mediated transcriptional activity. Furthermore, we showed that IFIXalpha1 promotes the ubiquitination of HDM2. Our data suggest that IFIXalpha1 functions as a tumor suppressor by negatively regulating HDM2. They also suggest that IFIXalpha1 mediates a novel crosstalk between IFN signaling pathway and HDM2-p53 auto-regulatory loop, and that may contribute in part to the IFN-induced anti-tumor activity in certain cancers.