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Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor
V R Chazin1, M Kaleko, A D Miller
1Department of Medicine, University of California, Los Angeles.
Abstract:
Amplification of the HER-2 (c-erbB-2) gene and overexpression of the p185HER-2 gene product is found in approximately one-third of primary human breast and ovarian cancers and is associated with a poor clinical outcome of early relapse and death. The HER-2 gene encodes a cell-surface growth factor receptor with intrinsic tyrosine kinase activity. Wild-type human HER-2 has been shown to act as a potent oncogene when over-expressed in mouse fibroblasts. Recent data suggest that the mechanism by which HER-2 mediates transformation requires the interaction of the epidermal growth factor (EGF) receptor. To test whether overexpression of normal human HER-2 can transform cells independently of the EGF receptor, we have introduced multiple copies of HER-2 into the EGF receptor-negative cell line, NR6, and have performed assays for both transformation and tumorigenicity. Engineered NR6 cells that overexpress the HER-2 gene product display a highly transformed and tumorigenic phenotype as compared with control cells. Additionally, a monoclonal antibody to the extracellular domain of the HER-2 receptor is able to inhibit the proliferation of the overexpressing cells in vitro as well as tumor growth in vivo. This study provides clear evidence that HER-2-mediated transformation can be achieved independently of the EGF receptor.
Insights
Amplification of the human epidermal growth factor receptor 2 (HER-2) gene drives cancer. This study shows HER-2 can transform cells independently of the epidermal growth factor receptor, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- HER-2 gene amplification and p185HER-2 overexpression occur in about one-third of human breast and ovarian cancers.
- HER-2 overexpression is linked to poor clinical outcomes, including early relapse and death.
- The HER-2 gene encodes a cell-surface growth factor receptor with tyrosine kinase activity, acting as a potent oncogene when overexpressed.
Purpose of the Study:
- To investigate if HER-2 can transform cells independently of the epidermal growth factor (EGF) receptor.
- To assess the role of HER-2 in cellular transformation and tumorigenicity.
Main Methods:
- Introduced multiple copies of the HER-2 gene into EGF receptor-negative NR6 cells.
- Performed transformation and tumorigenicity assays on engineered NR6 cells.
- Utilized a monoclonal antibody against the HER-2 receptor to inhibit cell proliferation and tumor growth.
Main Results:
- Engineered NR6 cells overexpressing HER-2 exhibited a significantly transformed and tumorigenic phenotype compared to controls.
- A monoclonal antibody targeting the HER-2 receptor effectively inhibited proliferation in vitro and tumor growth in vivo.
- Demonstrated that HER-2-mediated transformation is independent of the EGF receptor.
Conclusions:
- HER-2 overexpression can induce cellular transformation and tumorigenicity without the involvement of the EGF receptor.
- Targeting the HER-2 receptor with antibodies can inhibit cancer cell proliferation and tumor growth.
- These findings provide crucial evidence for HER-2 as a direct oncogenic driver and a potential therapeutic target in cancers independent of EGF receptor signaling.