Breast and
ovarian cancer are two of the leading causes of death for women in the United States. HER2/neu overexpression is an unfavorable prognosis factor associated with low patient survival rate of multiple
cancer types including breast and
ovarian cancer. Downregulation of the HER2/neu gene expression in
cancer cells has been shown to be a useful strategy to significantly reverse the malignant characteristics induced by HER2/neu overexpression. It is possible that HER2/neu overexpression can be repressed through inhibiting the promoter activity of the gene. We have identified a number of potent transcriptional regulators, including the adenovirus type 5 E1A, the SV40
large T antigen, and the ets family member PEA3, and have tested their activity to repress HER2/neu overexpression. Ectopic expression of these transcriptional regulators resulted in downregulation of the HER2/neu promoter activity and reversed the transformed phenotype of the
cancer cells in vitro. These observations were followed by a series of studies to investigate whether these HER2/neu repressors could act therapeutically as tumor suppressor genes for
cancers overexpressing HER2/neu. The results of these preclinical studies clearly indicated that transcriptional repressors, which downregulate HER2/neu overexpression, can be an effective regimen for
cancer treatment in a gene
therapy format combined with an appropriate gene delivery system such as the cationic
liposome DC-Chol or replication-deficient adenovirus vector. Our results have demonstrated that these delivery systems can effectively transfer the therapeutic genes into the
cancer cells in vivo and lead to significant suppressive effects on
tumor growth. Furthermore,
tumor-free survival rate of treated animals is increased dramatically using nontoxic doses, compared with animals without the treatment. A great body of evidence has revealed the potential of using transcriptional repressors to suppress HER2/neu overexpression and abolish
tumor growth. Thus, suppression of oncogenic gene expression using
transcription factors can be a novel field for
cancer treatment and prevention.