title: Reduced growth rate accompanied by aberrant epidermal growth factor signaling in drug resistant human breast cancer cells.
abstract: We examined transforming growth factor (TGF) alpha, epidermal growth factor (EGF) and EGF receptor (EGFR) expression and signaling in three drug resistant MCF-7 human breast cancer sublines and asked whether these pathways contribute to the drug resistance phenotype. In the resistant sublines, upregulation of both TGFalpha and EGFR mRNA was observed. In an apparent contrast with upregulated growth factor and receptor gene expression, the drug resistant sublines displayed a reduced growth rate. Defects in the EGFR signaling pathway cascade were found in all examined drug resistant sublines, including 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 of the stress-activated protein kinase activity was similar in both parental and drug resistant cells. Evaluating the link between the reduced growth rate and drug resistance, serum starvation experiments were performed. These studies demonstrated that a reduced proliferative activity resulted in a marked reduction in sensitivity to cytotoxic agents in the parental MCF-7 cells. We propose that the altered EGFR levels frequently observed in drug resistant breast cancer cells are associated with perturbations in the signaling pathway that mediate a reduced proliferative rate and thereby contribute to drug resistance.
authors.affiliation: Medicine Branch, Division of Clinical Science, NCI, NIH, Bldg. 10, Room 12N226, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wosikowski
authors.forename: J A
authors.initials: JA
authors.lastname: Silverman
authors.forename: P
authors.initials: P
authors.lastname: Bishop
authors.forename: J
authors.initials: J
authors.lastname: Mendelsohn
authors.forename: S E
authors.initials: SE
authors.lastname: Bates
mesh_terms: D000841:Anisomycin; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms; D002455:Cell Division; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D011233:Precipitin Tests; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D000841:Anisomycin; D004317:Doxorubicin; D048056:Mitogen-Activated Protein Kinase 9; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel