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Updated: Nov 25, 2025
Monitoring of Nanodrug Accumulation in Murine Breast Cancer Metastases
Published on: August 23, 2024
MEK1 Inhibitor Combined with Irradiation Reduces Migration of Breast Cancer Cells Including miR-221 and ZEB1 EMT
Nataša Anastasov1,2, Elisabeth Hirmer1,3, Marbod Klenner1
1Institute of Radiation Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Abstract:
The miR-221 expression is dependent on the oncogenic RAS-RAF-MEK pathway activation and influences epithelial-to-mesenchymal transition (EMT). The Cancer Genome Atlas (TCGA) database analysis showed high gene significance for ZEB1 with EMT module analysis and miR-221 overexpression within the triple-negative breast cancer (TNBC) and HER2+ subgroups when compared to luminal A/B subgroups. EMT marker expression analysis after MEK1 (TAK-733) inhibitor treatment and irradiation was combined with miR-221 and ZEB1 expression analysis. The interaction of miR-221 overexpression with irradiation and its influence on migration, proliferation, colony formation and subsequent EMT target activation were investigated. The results revealed that MEK1 inhibitor treatment combined with irradiation could decrease the migratory potential of breast cancer cells including reduction of miR-221 and corresponding downstream ZEB1 (EMT) marker expression. The clonogenic survival assays revealed that miR-221 overexpressing SKBR3 cells were more radioresistant when compared to the control. Remarkably, the effect of miR-221 overexpression on migration in highly proliferative and highly HER2-positive SKBR3 cells remained constant even upon 8 Gy irradiation. Further, in naturally miR-221-overexpressing MDA-MB-231 cells, the proliferation and migration significantly decrease after miR-221 knockdown. This leads to the assumption that radiation alone is not reducing migration capacity of miR-221-overexpressing cells and that additional factors play an important role in this context. The miR-221/ZEB1 activity is efficiently targeted upon MEK1 inhibitor (TAK-733) treatment and when combined with irradiation treatment, significant reduction in migration of breast cancer cells was shown.
Insights
MicroRNA-221 (miR-221) promotes breast cancer migration and radioresistance by activating ZEB1. Combining MEK1 inhibition with irradiation effectively reduces miR-221/ZEB1 activity and breast cancer cell migration.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MicroRNA-221 (miR-221) expression is linked to the RAS-RAF-MEK pathway and epithelial-to-mesenchymal transition (EMT).
- Overexpression of miR-221 and ZEB1 is observed in triple-negative breast cancer (TNBC) and HER2+ subtypes compared to luminal subtypes.
- miR-221 influences cancer cell migration, proliferation, and radioresistance.
Purpose of the Study:
- To investigate the role of miR-221 in breast cancer progression and its interaction with MEK1 inhibition and irradiation.
- To evaluate the therapeutic potential of targeting the miR-221/ZEB1 axis in breast cancer.
Main Methods:
- Analysis of TCGA database for gene significance and miRNA expression.
- Treatment of breast cancer cells with MEK1 inhibitor (TAK-733) and irradiation.
- Assessment of cell migration, proliferation, and colony formation.
- Analysis of miR-221, ZEB1, and EMT marker expression.
Main Results:
- MEK1 inhibitor treatment combined with irradiation reduced breast cancer cell migration, miR-221, and ZEB1 expression.
- miR-221 overexpressing cells exhibited increased radioresistance.
- Irradiation did not significantly reduce migration in miR-221 overexpressing cells, suggesting other factors are involved.
- miR-221 knockdown decreased proliferation and migration in MDA-MB-231 cells.
Conclusions:
- The miR-221/ZEB1 pathway is a key driver of breast cancer migration and radioresistance.
- Combined MEK1 inhibition and irradiation effectively targets the miR-221/ZEB1 axis, reducing breast cancer cell migration.
- Targeting miR-221 presents a potential therapeutic strategy for breast cancer treatment, particularly in resistant subtypes.
