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Basic science of HER-2/neu: a review
1Department of Cancer Biology, the University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Abstract:
The HER-2/neu (also known as c-erbB-2) oncogene is the second member of the epidermal growth factor receptor family. It is overexpressed in many different types of human cancers, including breast, ovarian, lung, gastric, and oral cancers. Overexpression of HER-2/neu in breast cancer has been associated with poor overall survival and has been shown preclinically to enhance malignancy and the metastatic phenotypes. Although discrepancies exist between different studies, HER-2/ neu overexpression seems to induce chemoresistance in certain experimental conditions. Many studies have convincingly shown that repression of HER-2/neu suppresses the malignant phenotypes of HER-2/neu-overexpressing cancer cells. These findings strongly suggest that HER-2/neu may serve as an excellent target for developing anticancer agents specific for HER-2/neu-overexpressing cancer cells. HER-2/neu-encoded p185 protein is a receptor tyrosine kinase that can be associated with multiple signal transduction pathways. However, it is not yet clear how a specific signal pathway may correspond to a specific biological response. This report reviews basic information on signal transduction of HER-2/neu receptor tyrosine kinase and summarizes our approaches to targeting HER-2/neu-overexpressing cancer cells. The HER-2/neu promoter was targeted using cationic liposomes or an adenovirus vector to deliver the adenovirus-5 EIA gene products and a nontransformed mutant of the SV40 large T antigen into the tumor-bearing mice. This resulted in suppression of the tumor growth and prolongation of survival. For repressing the function of HER-2/neu we used emodin, a tyrosine kinase inhibitor. This agent can inhibit the tyrosine kinase activity of HER-2/neu and preferentially block the growth of the HER-2/neu-overexpressing human breast cancer cells in tissue culture as well as in nude mice.
Insights
Targeting the HER-2/neu oncogene, overexpressed in many cancers, offers a promising strategy for developing new anticancer therapies. Inhibiting HER-2/neu, particularly in breast cancer, suppresses tumor growth and enhances survival.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The HER-2/neu (c-erbB-2) oncogene, part of the epidermal growth factor receptor family, is overexpressed in various human cancers, including breast, ovarian, lung, gastric, and oral cancers.
- HER-2/neu overexpression in breast cancer correlates with reduced survival and enhanced malignancy and metastasis.
- While its role in chemoresistance is debated, HER-2/neu overexpression is linked to resistance in some contexts.
Purpose of the Study:
- To review signal transduction pathways of the HER-2/neu receptor tyrosine kinase.
- To summarize strategies for targeting HER-2/neu-overexpressing cancer cells.
- To evaluate novel therapeutic approaches for HER-2/neu-driven cancers.
Main Methods:
- Targeting the HER-2/neu promoter using cationic liposomes or adenovirus vectors to deliver specific genes (adenovirus-5 EIA, SV40 large T antigen mutant).
- Utilizing emodin, a tyrosine kinase inhibitor, to repress HER-2/neu function.
- Assessing tumor growth suppression and survival prolongation in tumor-bearing mice.
- Evaluating the effect of emodin on HER-2/neu-overexpressing human breast cancer cells in vitro and in vivo.
Main Results:
- Delivery of therapeutic genes via liposomes or adenovirus vectors suppressed tumor growth and prolonged survival in mice.
- Emodin effectively inhibited HER-2/neu tyrosine kinase activity.
- Emodin preferentially inhibited the growth of HER-2/neu-overexpressing human breast cancer cells in tissue culture and in nude mice models.
Conclusions:
- HER-2/neu is a viable therapeutic target for cancers exhibiting its overexpression.
- Gene therapy approaches targeting the HER-2/neu promoter show potential for cancer treatment.
- Tyrosine kinase inhibitors like emodin can effectively suppress the growth of HER-2/neu-overexpressing cancers.