Targeting Human Breast Cancer Cells That Overexpress HER-2/neu mRNA by an Antisense Iron Responsive Element
Annual rept. 1 Jun 2001-31 May 2002
M D ANDERSON CANCER CENTER HOUSTON TX
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In this project, we attempt to establish the utility of an antisense iron-responsive element AS-IRE-mediated gene expression system to targeting HER-2neu-overexpressing breast cancer cells. During the first two years of funding, we have finished the proposed goal stated in Task 1 by identifying the optimal HER-2neu antisense IRE, i.e., AS-IRE4. Moreover, we showed preferential cell killing in HER-2neu-overexpressing MDA-MB-453 cells using hTERT-AS-IRE4-Bax as opposed to in low HER-2neu-expressing MDA-MB-468 cells Task 2. The results obtained from Task 1 and 2 have been published in Cancer Letters 174151-158, 2001. To test the therapeutic efficacy of the hTERT-AS-IRE4-luc in a pre-clinical gene therapy model Task 3, our next goal is to use a binary adenoviral vector Bax gene expression system to test the preferential killing of HER-2-overexpressing breast cancer cells in vitro and in vivo. To demonstrate the feasibility of adenovirus-based gene therapy in our orthotopic breast cancer xenograft model, we showed that adenoviral vector-mediated therapeutic gene transfer could yield treatment efficacy as indicated by our recent publication in Clinical Cancer Research 83290-3297, 2002. In addition, we have staffed to explore the possibility of using small interference RNA SiRNA as a novel approach to specific target HER-2-overexpressing cells. Our preliminary results suggested that SiRNA is potentially a powerful technology to achieve specific downregulation of HER-2neu gene.
- Anatomy and Physiology
- Medicine and Medical Research