Modulation of Epidermal Growth Factor Receptor Expression by Chemotherapeutic Agents in Breast Cancer Cell Lines.

摘要

The epidermal growth factor receptor (EGFR) 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 EGFR 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 EGFR in breast cancer cells with the hope of explaining why higher levels of EGFR & common to more advanced breast tumors. We have shown that exposure of MCF-7, TATh, and ZR-75-1 breast cancer cells to the anti-metabolite compound methotrexate causes an u%regulation of EOFR receptor expression. Our work demonstrates that the ECFER up-re gulati on usually occurs at both the mRNA level and protein level (with increased expression on the cell surface) and that this may be accompanied by changes in the expression of E iFR ligands. We are currently performing experiments to determine whether methotrexate-induced EGFR expression in these cells alters EOF-mediated phosphorylation of ERK and AKT (causing changes in the specificity, timing and intensity of EGFR signaling through these pathways in a cell specific manner). ERK and AKT signaling pathways have been shown to mediate anti- apoptotic effects. In addition, we are investigating the potential role for increased E&FR expression and signaling in cell survival by suppression of chemotherapy induced apoptosis.