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Plasma membrane phosphotyrosine, Her2-NEU, and epidermal growth factor receptor in human breast cancer. A comparative
S C Heffelfinger1, E E Lower, M A Miller
1Department of Pathology and Laboratory Medicine, University of Cincinnati, OH 45267-0529, USA.
Abstract:
Experimental therapeutic regimens for breast cancer include strategies to block the activity of specific oncogenes. Because oncogenesis is a multistep process, specific oncogenes may drive tumor production at one stage yet not function in another. Since the effectiveness of therapy targeted against oncogenes depends on their function in the tumor, correlation of oncogene function to specific stages of tumor development has therapeutic implications. Among the oncogenes known to be important in breast cancer production are two cell surface growth factor receptors, epidermal growth factor receptor (EGFR) and Her2-NEU (NEU). These proteins are receptor tyrosine kinases that autophosphorylate specific tyrosine residues on activation. The oncogenic potential of these receptors depends on this autophosphorylation. We examined 86 primary formalin-fixed, paraffin-embedded breast tumors for overexpression of EGFR and NEU and correlated our findings with the presence of cell surface phosphotyrosine as an indicator of tyrosine kinase activity at the plasma membrane. Our data indicate that only 34% of tumors that overexpress EGFR or NEU show plasma membrane phosphotyrosine, indicating that in the majority of these tumors, the overexpressed oncogene may not be active at this stage.
Insights
Targeted breast cancer therapies may be less effective than expected. Many tumors overexpressing growth factor receptors like EGFR and Her2-NEU show no active signaling, suggesting the oncogenes are not functional at this stage.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Breast cancer treatment often targets oncogenes, but their activity can vary during tumor development.
- Epidermal growth factor receptor (EGFR) and Her2-NEU are key oncogenes in breast cancer, functioning as receptor tyrosine kinases.
- Therapeutic success relies on targeting active oncogenes, necessitating an understanding of their functional state in tumors.
Purpose of the Study:
- To investigate the correlation between EGFR and Her2-NEU overexpression and their functional activity in breast tumors.
- To determine the prevalence of active tyrosine kinase signaling at the plasma membrane in tumors with EGFR or Her2-NEU overexpression.
Main Methods:
- Analysis of 86 primary formalin-fixed, paraffin-embedded breast tumors.
- Assessment of EGFR and Her2-NEU overexpression.
- Detection of cell surface phosphotyrosine as a marker of tyrosine kinase activity.
Main Results:
- Overexpression of EGFR or Her2-NEU was observed in a subset of breast tumors.
- Only 34% of tumors with EGFR or Her2-NEU overexpression exhibited detectable plasma membrane phosphotyrosine.
- This suggests that in the majority of cases, overexpressed oncogenes may not be functionally active at the cell surface.
Conclusions:
- A significant proportion of breast tumors overexpressing EGFR or Her2-NEU may not rely on these oncogenes for active signaling.
- These findings have critical implications for the efficacy of targeted therapies directed against these specific oncogenes.
- Further research is needed to understand the functional status of oncogenes in different stages of breast cancer development.