Modulation of Epidermal Growth Factor Receptor Expression by Chemotherapeutic Agents in Breast Cancer Cell Lines
Abstract
The epidermal growth factor receptor (EOFR) is a cell-surface protein that relays signals from the extracellular environment into the cell by binding specific polypeptide hormones followed by activation of intracellular signal transduction pathways. Although rarely an oncogene, the ability of EGFR-mediated signaling to generate diverse responses including growth, differentiation, stress response, apoptosis suppression, and altered mobility makes this protein a potentially powerful tumor promoter. The association between higher EOFR expression and poorer prognosis in breast cancer and the frequency of higher EGFR levels in more aggressive/metastatic breast tumors reinforce this possibility. Our research aims to uncover a link between chemotherapeutic exposure and increased expression of EOFR in breast cancer cells with the hope of explaining why higher levels of EGFR are common to more advanced breast tumors. We have shown that exposure of MCF-7, T-47D, and ZR-75-1 breast cancer cells to the anti-metabolite compound methotrexate causes an up-regulation of EGFR receptor expression. Our work demonstrates that the EGFR up-regulation usually occurs at both the niRNA level and protein level (with increased expression on the cell surface) and that this may be accompanied by changes in the expression of EGFR ligands. We also demonstrate that the methotrexate-induced EOFR expression in these cells alters EGF-mediated phosphorylation of ERK and AKT (causing changes in the specificity, timing and intensity of EOFR signaling through these pathways in a cell specific manner). ERK and AKT signaling pathways have been shown to mediate anti-apoptotic effects. We therefore hypothesize that increased EOFR expression and signaling in these cells provides a survival advantage by suppression of chemotherapy induced apoptosis, possibly explaining the prevalence of EGFR over-expression in drug resistant cell lines and more aggressive breast tumors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2002
- Accession Number
- ADA409651
Entities
People
- James N. Welch
Organizations
- Georgetown University