Radiation promotes malignant phenotypes through SRC in breast cancer cells.
Bottom Line: However, the molecular mechanisms underlying radiation-induced cancer progression remain obscure.Importantly, radiation-activated SRC induced SLUG expression and caused epithelial-mesenchymal cell transition through phosphatidylinositol 3-kinase/protein kinase B and p38 MAPK signaling.In addition, downregulation of SRC also abolished radiation-acquired resistance of breast cancer cells to anticancer agents such as cisplatin, etoposide, paclitaxel, and IR.
Affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.Show MeSH
Related in: MedlinePlus
Mentions: To study the harmful effects of radiotherapy, we examined whether IR causes breast cancer cells to acquire migratory and invasive properties. To this end, MCF7 and SKBR3 breast cancer cell lines were exposed to fractionated doses of radiation (2 Gy ×3; 2 Gy/day for 3 days). Cancer cells were then applied to migration and invasion assays that were carried out by counting migrated cells in Transwells that had been pre-coated with Matrigel (invasion assay) or left uncoated (migration assay). By these analysis, we observed that exposure to radiation enhances the migratory and invasive properties of breast cancer cells (Fig.1a). As the migratory and invasive behavior of cancer cells is often associated with EMT, we next examined the effect of radiation on expression levels of EMT markers such as E-cadherin, N-cadherin, and vimentin. Importantly, the expression of E-cadherin was decreased, whereas N-cadherin and vimentin were increased 48 h after irradiation (Fig.1b,c). We also examined expression levels of EMT transcription factors such as SNAIL, SLUG, ZEB1, and TWIST after irradiation of breast cancer cells. In line with the above data, irradiation caused an increase of SLUG; however, other EMT transcription factors were not altered by irradiation (Fig.1d). To test whether radiation-induced EMT is mainly caused by SLUG, we examined migratory and invasive properties of MCF7 breast cancer cells after treatment with siRNA targeting SLUG prior to irradiation. Of note, downregulation of SLUG effectively attenuated radiation-induced migratory and invasive properties of breast cancer cells Fig. S1a). In agreement with this result, downregulation of SLUG also blocked radiation-induced EMT markers (Fig. S1b,c). Taken together, these results suggest that irradiation causes breast cancer cells to acquire migratory and invasive properties by inducing SLUG and thereby triggering the EMT program.
Affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.