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Increased epidermal growth factor receptor in an estrogen-responsive, adriamycin-resistant MCF-7 cell line
B Dickstein1, E M Valverius, K Wosikowski
1Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892.
Abstract:
We examined the expression of the estrogen and epidermal growth factor (EGF) receptors in a drug-resistant subline of MCF-7 cells in order to study potential alterations in hormone dependence or in the growth factor pathway that could be related to the development of drug resistance in human breast cancer. The drug-resistant subline was derived from MCF-7 cells by selection with Adriamycin in the presence of the P-glycoprotein antagonist, verapamil, to prevent acquisition of the classical multidrug resistance phenotype. The Adriamycin-resistant cells retain estrogen-binding, estrogen-responsive monolayer growth, and estrogen-dependent tumorigenesis. Estrogen-binding studies demonstrate 1.4 x 10(6) sites per cell with unaltered affinity when compared to parental MCF-7 cells, which have 2.7 x 10(5) sites per cell. An increase in expression of EGF receptor, eight to 12-fold, occurred early in the selection for drug resistance, and appears to be unrelated to verapamil exposure, since cells maintained in Adriamycin without verapamil also have increased EGF receptor expression. Partially drug-sensitive revertants carried a verapamil, but out of Adriamycin, demonstrate a decline in EGF receptor expression. We postulate that activation of growth factor pathways in drug-resistant cells may enhance mechanisms of drug resistance, or provide mitogenic stimuli for cells to recover after damage by drug exposure.
Insights
Drug resistance in breast cancer cells involves increased epidermal growth factor (EGF) receptor expression. This suggests growth factor pathways may play a role in overcoming chemotherapy, impacting human breast cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Drug resistance is a major challenge in human breast cancer treatment.
- Understanding alterations in hormone and growth factor pathways is crucial for overcoming resistance.
Purpose of the Study:
- To investigate changes in estrogen and epidermal growth factor (EGF) receptor expression in Adriamycin-resistant MCF-7 breast cancer cells.
- To explore the relationship between these receptor alterations and the development of drug resistance.
Main Methods:
- Developed an Adriamycin-resistant MCF-7 subline using verapamil to prevent classical multidrug resistance.
- Assessed estrogen receptor binding and expression.
- Quantified EGF receptor expression levels using quantitative methods.
Main Results:
- Adriamycin-resistant cells maintained estrogen responsiveness and tumorigenesis.
- Estrogen receptor expression increased significantly (1.4 x 10^6 sites/cell vs. 2.7 x 10^5 sites/cell).
- EGF receptor expression increased 8-12 fold early in resistance development, independent of verapamil.
Conclusions:
- Increased EGF receptor expression in drug-resistant breast cancer cells suggests a role for growth factor pathways in resistance mechanisms.
- Activation of growth factor signaling may enhance drug resistance or promote cell recovery after drug damage.
- Targeting growth factor pathways could be a potential strategy to overcome drug resistance in human breast cancer.