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Reduced growth rate accompanied by aberrant epidermal growth factor signaling in drug resistant human breast cancer cells.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2000 Jul 21; Vol. 1497 (2), pp. 215-26. - Publication Year :
- 2000
-
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.
- Subjects :
- Anisomycin
Antineoplastic Agents pharmacology
Breast Neoplasms
Cell Division
Cell Line
DNA-Binding Proteins genetics
DNA-Binding Proteins isolation & purification
Doxorubicin pharmacology
Drug Resistance
ErbB Receptors drug effects
Humans
Immunoblotting
Mitogen-Activated Protein Kinase 9
Mitogen-Activated Protein Kinases metabolism
Paclitaxel pharmacology
Phenotype
Precipitin Tests
Proto-Oncogene Proteins c-fos genetics
RNA, Messenger analysis
Signal Transduction
Tumor Cells, Cultured
DNA-Binding Proteins metabolism
Epidermal Growth Factor metabolism
ErbB Receptors metabolism
Transforming Growth Factor alpha metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1497
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 10903426
- Full Text :
- https://doi.org/10.1016/s0167-4889(00)00062-8