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Drug resistant breast cancer cells overexpress ETS1 gene
Meltem Demirel Kars1, Ozlem Darcansoy Işeri, Ufuk Gündüz
1Department of Biological Sciences, Middle East Technical University, Eskisehir Yolu, 06531 Ankara, Turkey.
Purpose:
Multidrug resistance (MDR) is resistance to wide range of structurally unrelated anticancer agents. MDR is a serious limitation to the effective chemotherapy. Involvement of ETS1 overexpression in upregulation of MDR1 gene expression is implicated. In the present study the aim was to assess the involvement of ETS1 and the genes, which encode the proteins interacting with ETS1 in drug resistant MCF-7 breast cancer cells.
Methods:
Drug resistant sublines to paclitaxel (MCF-7/Pac), docetaxel (MCF-7Doc), vincristine (MCF-7/Vinc) and doxorubicin (MCF-7/Dox) that were developed from sensitive MCF-7 cells (MCF-7/S) were used. cDNA microarray analysis was performed for the RNA samples of sensitive and resistant cells in duplicate experiments. GeneSpring GX 7.3.1 Software was used in data analysis. Microarray data was supported by immunocytochemistry and western blot for drug resistance protein, P-gp, encoded by MDR1 gene.
Results:
According to microarray data MDR1 and ETS1 genes were highly overexpressed in all of the resistant sublines. Matrix metalloproteinase-1 gene (MMP-1) was also tremendously upregulated only in vincristine resistant cells. Immunocytochemistry and western blot results confirmed that P-gp was highly overexpressed in resistant sublines compared to original MCF-7 cells.
Conclusion:
High ETS1 expression levels in all resistant MCF-7 sublines may lead to the upregulation of the transcription of MDR1 gene. Overexpression of ETS1 gene in resistant cells may have contributed to the development of resistance in the cells. Furthermore, the significant upregulation of MMP1 and MMP9 in MCF-7/Vinc may also be related to an acquired invasive behavior of MCF-7 cell line due to vincristine treatment.
Insights
Multidrug resistance (MDR) in breast cancer cells involves ETS1 overexpression, leading to increased MDR1 gene expression. This study investigated ETS1 and interacting genes in drug-resistant MCF-7 cells, confirming ETS1
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Multidrug resistance (MDR) significantly limits chemotherapy efficacy.
- ETS1 overexpression is implicated in the upregulation of the MDR1 gene, contributing to MDR.
- Understanding the molecular mechanisms of MDR in breast cancer is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of ETS1 and its interacting genes in drug-resistant MCF-7 breast cancer cells.
- To assess the expression levels of ETS1 and MDR1 in various drug-resistant sublines.
- To explore potential mechanisms underlying acquired chemoresistance.
Main Methods:
- Development of drug-resistant MCF-7 sublines (MCF-7/Pac, MCF-7Doc, MCF-7/Vinc, MCF-7/Dox).
- cDNA microarray analysis to compare gene expression between sensitive (MCF-7/S) and resistant cells.
- Immunocytochemistry and western blot to confirm P-gp (MDR1) overexpression.
Main Results:
- MDR1 and ETS1 genes were significantly overexpressed in all drug-resistant MCF-7 sublines.
- Matrix metalloproteinase-1 (MMP-1) was upregulated specifically in vincristine-resistant cells.
- P-glycoprotein (P-gp) was confirmed to be overexpressed in resistant cells, validating MDR1 upregulation.
Conclusions:
- High ETS1 expression likely drives MDR1 transcription, contributing to multidrug resistance in MCF-7 cells.
- ETS1 overexpression may be a key factor in the development of chemoresistance.
- Upregulation of MMP1 and MMP9 in vincristine-resistant cells suggests potential acquired invasive behavior.
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