Radiation-induced exosomal miR-21 enhances tumor proliferation and invasiveness in breast cancer: implications for poor prognosis in radiotherapy patients

Radiotherapy is widely used as an effective non-surgical strategy to control malignant tumors. However, recurrence is one of common causes of treatment failure even after the effective radiotherapy. In this study, we focused on the effects of radiation-induced exosomal miR-21 on the tumor microenvironment to investigate the causes of recurrence. Analysis of the TCGA database revealed that breast cancer patients with high levels of miR-21 have significantly reduced overall survival when treated with radiotherapy compared to those who did not receive radiotherapy, indicating a high hazard ratio for miR-21 in patients undergoing this treatment. Additionally, exosomal miR-21 is found to be highly expressed in the serum of breast adenocarcinoma patients. To explore how miR-21 induces poor prognosis in irradiated breast cancer, we irradiated 4T1 cell line with low or high doses of radiation, and examined the impact of secreted exosomal miR-21 on breast cancer cell and tumor microenvironment. After 10 Gy irradiation, 4T1 cells secreted 2.20 ± 0.10 times more exosomes and exhibited a 1.85 ± 0.01-fold increase in exosomal miR-21 levels. Treatment with exosomes from 10 Gy-irradiated cancer cells led to enhanced tumor cell proliferation, wound healing, and migration. The survival rate of 10 Gy-irradiated tumor cells incubated with 10 Gy-derived exosomes increased by 2.83-fold. Moreover, the growth of subcutaneous tumors treated with 10 Gy exosomes (n = 13) was significantly faster compared to tumors treated with 0 Gy exosomes (n = 10, P < 0.05). In summary, our study revealed high-dose irradiation-induced exosomes were found to enhance tumor proliferation and invasiveness via the transfer of exosomal miR-21. Based on these findings, we suggest that radiation-induced exosomal miR-21 may contribute to a poorer prognosis of breast cancer patients undergoing radiotherapy.