Abstract
Breast and ovarian cancers are the leading cause of death for women in many areas in the world including the United States. Overexpression of the HER-2/neu gene (also known as c-erbB2) is a frequent event in about 30% of breast as well as ovarian cancers. The overall survival rates of breast and ovarian cancer patients whose tumors overexpress HER-2/neu are significantly lower than those of patients whose tumors do not overexpress HER-2/neu. Overexpression of HER-2/neu leads to elevated tumorigenicity, enhanced metastatic potential, increased resistance to TNF-α-induced apoptosis and resistance to treatments such as paclitaxel and tamoxifen. Down-regulation of the HER-2/neu oncogene causes suppression of the cell-transforming phenotype induced by the oncogene. For example, downregulation of the HER-2/neu gene expression by E1A significantly mitigated tumorigenic activity of human breast and ovarian cancer cells in nude mice. These results strongly imply that HER-2/neu mediated cell transformation may be inhibited by transcriptional repressors that target the promoter of the oncogene. In addition to E1A, we recently identified the ets transcription factor PEA3 as a potential HER-2/neu gene inhibitor. PEA3 binds directly to this consensus binding motif and suppresses the HER-2/neu gene promoter activity. Downregulation of HER-2/neu expression led to inhibition of cell transformation and proliferation in vitro. In a preclinical gene therapy setting, in which the PEA3 gene tumor delivery was facilitated by a cationic liposome DC-Chol, blocked HER-2/neu overexpression by PEA3 resulted in prolonged survival of treated animals. These studies demonstrate a promising approach to cancer gene therapy using transcriptional repressors to target expression of oncogenes such as HER-2/neu.
Original language | English (US) |
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Pages (from-to) | 835-843 |
Number of pages | 9 |
Journal | Drugs of Today |
Volume | 36 |
Issue number | 12 |
State | Published - 2000 |
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)