ERBB-Receptors and Drug Response in Breast Cancer
Abstract
We have previously shown that transfection of heregulin Beta-2 into MCF-7 breast cancer cells leads to activation of the ErbB2,3 and 4 receptors and upregulation of topoisomerase II (topo II)with a two log-fold increase in sensitivity to topo II inhibitors (doxorubicin, VP-16). The purpose of this work is to elucidate the relationship between signal transduction through the ErbB family of receptors and chemotherapy response to drugs used in breast cancer. Using our EGFR-ErbB2 chimeric receptor model we have confirmed that activation of the ErbB2 tyrosine kinase is associated with increase in topo II protein at 48, 72 and 96 hours post receptor activation. We have also observed an increase in topo II phosphorylation on tyrosine, previously unreported. Receptor activation leads to increased topo II cleavage activity and increased sensitivity to doxorubicin. Breast cancer cell lines overexpressing the ErbB2 receptor were treated with EGF, heregulin Beta-2 and 4D5 antibody directed against ErbB2. Although EGF and heregulin can slightly increase tyrosine phosporylation of these receptors, no significant change in topo II levels or phosphorylation were seen. Interestingly, when 4D5 antibody is applied to these cells there is a direct correlation of decrease in tyrosine kinase activity with topo II protein level and phosphorylation on tyrosine. Drug resistance to doxorubicin is also induced as expected. Taken together, these data suggest that activation of the ErbB2 receptor leads to increase in topo II protein level and phosphorylation which corresponds to an increase in sensitivity to doxorubicin. Whether specific residues on topo II are tyrosine phosphorylated upon growth factor activation which may lead to specific response to chemotherapy drugs is intriguing and will be further explored.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 1997
- Accession Number
- ADB232291
Entities
People
- Lyndsay N. Harris
Organizations
- Georgetown University