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Mek1 inhibitor combined with irradiation reduces migration of breast cancer cells including mir-221 and zeb1 emt marker expression.

Cancers 12:3760 (2020)
Publ. Version/Full Text Research data DOI
Open Access Gold
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords 3d-microtissue Assays ; Breast Cancer And Radiation ; Mek1 Inhibitor (tak-733) ; Migration Assays ; Mir-221 ; Zeb1; Tamoxifen Resistance; Kinase; Transduction
ISSN (print) / ISBN 2072-6694
Journal Cancers
Quellenangaben Volume: 12, Issue: 12, Pages: , Article Number: 3760 Supplement: ,
Publisher MDPI
Publishing Place St Alban-anlage 66, Ch-4052 Basel, Switzerland
Reviewing status Peer reviewed
Grants EP2820138A1/WO2013127964A1
Sirion Biotech (Martinsried, Germany)