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Transcriptional targeting of the HER-2/neu oncogene
1Department of Molecular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
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-alpha-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.
Insights
Targeting HER-2/neu overexpression with transcriptional repressors like PEA3 shows promise for breast and ovarian cancer gene therapy. Down-regulating this oncogene inhibits tumor growth and improves survival rates in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Breast and ovarian cancers are leading causes of death in women globally.
- Overexpression of the HER-2/neu (c-erbB2) gene occurs in ~30% of these cancers, correlating with poorer survival and treatment resistance.
- HER-2/neu overexpression enhances tumor growth, metastasis, and resistance to apoptosis and therapies like paclitaxel and tamoxifen.
Purpose of the Study:
- To investigate the potential of transcriptional repressors in inhibiting HER-2/neu oncogene expression and its associated cancer phenotypes.
- To evaluate the efficacy of the ets transcription factor PEA3 as a HER-2/neu inhibitor.
- To assess the therapeutic potential of PEA3-mediated gene therapy in preclinical cancer models.
Main Methods:
- Investigated the effect of down-regulating HER-2/neu expression using agents like E1A and the transcription factor PEA3.
- Assessed the binding of PEA3 to the HER-2/neu gene promoter and its impact on promoter activity.
- Evaluated the inhibition of cancer cell transformation and proliferation in vitro.
- Conducted preclinical gene therapy studies using PEA3 delivered via cationic liposomes (DC-Chol) in animal models.
Main Results:
- Down-regulation of HER-2/neu expression, including by PEA3, suppressed cancer cell transformation and proliferation.
- PEA3 directly binds to the HER-2/neu gene promoter, inhibiting its activity.
- Preclinical gene therapy with PEA3 demonstrated prolonged survival in treated animals by blocking HER-2/neu overexpression.
- E1A-mediated HER-2/neu down-regulation reduced tumorigenic activity of cancer cells in vivo.
Conclusions:
- Transcriptional repressors targeting the HER-2/neu oncogene promoter offer a viable strategy for cancer therapy.
- PEA3 is identified as a novel inhibitor of HER-2/neu, demonstrating therapeutic potential.
- Gene therapy utilizing transcriptional repressors like PEA3 presents a promising approach for treating HER-2/neu-overexpressing breast and ovarian cancers.