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Amplified expression of the HER2/ERBB2 oncogene induces resistance to tumor necrosis factor alpha in NIH 3T3 cells
R M Hudziak1, G D Lewis, M R Shalaby
1Department of Developmental Biology, Genentech, Inc., San Francisco, CA 94080.
Abstract:
Functional characterization of oncogene products that induce cellular transformation has progressed rapidly in recent years. However, less is known about the mechanism(s) by which the transformed cells may escape destruction by host immune defenses and form tumors. A recently described oncogene that has an important association with aggressive human breast carcinoma is "HER2," for human epidermal growth factor receptor 2. The oncogene has also been called NGL and human c-erbB-2 (ERBB2). In this paper we show that amplification of HER2 oncogene expression can induce resistance of NIH 3T3 cells to the cytotoxic effects of recombinant tumor necrosis factor alpha (rTNF-alpha) or macrophages. Resistance is accompanied by an increased dissociation constant for rTNF-alpha binding to high-affinity receptors on the HER2-transformed NIH 3T3 cells. The resistance phenotype is independent of transformation since NIH 3T3 cells transformed by the activated human homologue of the Harvey-ras oncogene (HRAS) retain high-affinity binding sites for rTNF-alpha as well as sensitivity to its cytotoxic effects. These results suggest that HER2 may potentiate tumorigenesis by inducing tumor cell resistance to host defense mechanisms.
Insights
The HER2 oncogene, linked to aggressive breast cancer, helps tumor cells evade immune destruction. HER2-transformed cells resist tumor necrosis factor alpha (TNF-alpha) and macrophage attacks.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cellular transformation by oncogenes is well-studied, but mechanisms of immune evasion by transformed cells are less understood.
- HER2 (human epidermal growth factor receptor 2), also known as ERBB2, is associated with aggressive human breast carcinoma.
Purpose of the Study:
- To investigate how HER2 oncogene expression affects the resistance of cells to immune defense mechanisms.
- To determine if HER2-mediated resistance is linked to transformation or specific receptor binding properties.
Main Methods:
- Amplification of HER2 oncogene expression in NIH 3T3 cells.
- Assessment of cell resistance to recombinant tumor necrosis factor alpha (rTNF-alpha) and macrophages.
- Analysis of rTNF-alpha binding affinity to high-affinity receptors.
Main Results:
- Amplified HER2 expression conferred resistance to rTNF-alpha and macrophages in NIH 3T3 cells.
- This resistance correlated with an increased dissociation constant for rTNF-alpha binding.
- NIH 3T3 cells transformed by Harvey-ras oncogene (HRAS) remained sensitive to rTNF-alpha, indicating HER2-specific effects.
Conclusions:
- HER2 oncogene amplification can induce resistance to host immune defenses.
- This resistance mechanism may involve altered TNF-alpha receptor binding.
- HER2 may promote tumorigenesis by enabling tumor cells to evade immune surveillance.