Role of EGF Receptor Negative Regulatory Components in Breast Cell Growth

摘要

Amplification of the epidermal growth factor receptor (EGF-R) in breast cancer portends a poor prognosis. We utilized a cell culture model based on the MDA-MB-468 (468) cell line to address the mechanism by which receptor amplification can increase receptor activation in cancer and provide a cellular growth advantage. We show that amplification of the EGF-R is accompanied by a corresponding increase in the number of activated EGF-R per cell. This increased level of EGF%-R activation is autocrine ligand dependent and is associated with an increased sensitivity to autocrine loop interruption. However, the increased receptor activity was not due to an elevated level of autocrine ligand production. We found that the EGF-R negative regulatory controls including internalization, downregulation, desensitization and phosphatase activity did not become limiting following receptor amplification. In contrast, we show that receptor amplification increases the ability of a cell to capture autocrine ligand. This increase in capture efficiency can account for the increased level of activation. Although the increased EGF-R activity following EGF-R amplification is ligand dependent, we also show that amplification of Her2 may increase the level of EGF-R activation in a ligand independent fashion. This would suggest that Her2 amplification promotes increased activity by some other mechanism.