ERBB-Receptors and Drug Response in Breast Cancer
Abstract
There is a compelling need for better ways to select cytotoxic therapy for a given patient with breast cancer. The role of the members of the type 1 growth factor receptor family (erbB1-4) and their ligands in predicting response to chemotherapy is still unknown. Clinical data support the role of the erbB2 receptor in resistance to some chemotherapeutic agents, mainly alkylators, while a dose-response effect to a doxorubicin-containing regimen has been seen. One potential explanation for this finding is our observation of upregulation of topoisomerase II (topo II) and sensitivity to doxorubicin, in cells in which the erbB2 and erbB3 and erbB4 receptors have been activated by the growth factor heregulin. Using EGFR-erbB chimera cells activated by EGF, we will determine which receptor is responsible for the phenotype of change in topo II levels and drug sensitivity. In addition, breast cancer cell lines with known expression of erbB receptors will be stimulated with EGF, amphiregulin and heregulin growth factors and topoisomerase changes will be measured. We also propose to examine the expression and activity of the topo II enzyme after erbB2 overexpressing cells are exposed to anti-erbB2 antibodies, many of which cause receptor phosphorylation. This allows us to explore the mechanism of topo II upregulation in cells with activated erbB receptors using a product with potential therapeutic efficacy. We will attempt to elucidate the mechanism of changes in topo II with erbB signalling by examining levels of DNA repair enzymes, changes in cell cycle and topo II promotor regulation. These studies will allow selection of erbB2 positive patients appropriate therapy to improve outcome and minimize toxicity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 1999
- Accession Number
- ADA385679
Entities
People
- Lynday Heria
Organizations
- Georgetown University