Abstract
Simple SummaryCombined chemotherapy and radiotherapy are an effective treatment for invasive breast cancer. However, some studies suggest that such interventions may increase the risk of metastasis. Cell metastatic behavior is highly dependent on RAS-RAF-MEK pathway and its downstream target activation, including miR-221 overexpression and epithelial-to-mesenchymal transition (EMT). By using MEK1 inhibitor (TAK-733) in combination with radiation therapy for breast cancer cells, significant decrease in migration capacity, including reduction of miR-221 and EMT (ZEB1) marker expression was observed. miR-221 holds great potential as therapeutic biomarker and target for new drug developments, however more insight into efficiency of miR-221 inhibition needs to be followed in the future.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.
Highlights
Adjuvant radiation therapy for breast cancer improves disease-free survival and overall survival [1]
We have previously shown that the expression of miR-221 was associated with higher risk of metastasis in advanced breast cancers [10] and miR-221 was considered to be a prognostic marker for distinguishing subgroups in advanced breast cancers [10]
Within The Cancer Genome Atlas (TCGA) database 512 samples were analyzed for miR-221 expression including different breast cancer subgroups: human epidermal growth factor receptor-2 (HER2)+, Luminal A, Luminal B and triple-negative breast cancer (TNBC) (Figure 1a, right)
Summary
Adjuvant radiation therapy for breast cancer (stage I–III) improves disease-free survival and overall survival [1]. There is no standard therapy for the breast cancer patients with recurrent or metastatic (advanced) breast cancer and it remains a great challenge to select an appropriate treatment [4,5]. One of the signaling pathways involved in tumor progression and EMT regulation is the RAS-RAF-MEK-MAPK pathway [6,7]. These kinases are overexpressed and hyperactive in various types of cancer. They regulate diverse cellular processes such as proliferation, migration, metastasis, resistance to chemotherapy, and EMT [8]
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