Reduced growth rate accompanied by aberrant epidermal growth factor signaling in drug resistant human breast cancer cells

We examined transforming growth factor (TGF) alpha, epidermd growth factor (EGF) and EGF receptor (EGFR) expression and signaling in three drug resist ant MCF-7 human breast cancer sublines and asked whether these pathways con tribute to the drug resistance phenotype. In the resistant sublines, upregu lation of both TGF alpha and EGFR mRNA was observed. In an apparent contras t with upregulated growth factor and receptor gene expression, the drug res istant sublines displayed a reduced growth rate. Defects in the EGFR signal ing pathway cascade were found in all examined drug resistant sublines, inc luding altered EGF-induced Shc, Raf-1, or mitogen-activated protein kinase phosphorylation. Induction of c-fos mRNA expression by EGF was impaired in the sublines compared to parental MCF-7 cells. In contrast, the induction o f the stress-activated protein kinase activity was similar in both parental and drug resistant cells. Evaluating the link between the reduced growth r ate and drug resistance, serum starvation experiments were performed. These studies demonstrated that a reduced proliferative activity resulted in a m arked reduction in sensitivity to cytotoxic agents in the parental MCF-7 ce lls. We propose that the altered EGFR levels frequently observed in drug re sistant breast cancer cells are associated with perturbations in the signal ing pathway that mediate a reduced proliferative rate and thereby contribut e to drug resistance. (C) 2000 Elsevier Science B.V. All rights reserved.