Src Kinase Activates Signal Transducer and Activator of Transcription 3 to Enhance Radioresistance in Triple Negative Breast Cancer Cells

Abstract

Triple-negative breast cancer (TNBC) is known to be insensitive to radiation therapy, and it requires to development radiosensitizer for TNBC. We previously established a radioresistant sub-line from MDA-MB-231 cells, called 231-RR, and have demonstrated that 231-RR cells displayed high cancer stem cell (CSC) activity. And 231-RR cells were treated with dasatinib, a Src inhibitor. In the present study, we discovered that the activation of Src kinase was increased in 231-RR cells. Treatment of dasatinib, an Src inhibitor, sensitized 231-RR cells to radiotherapy, along with the increased p-γH2Axser139, indicated the enhancement of DNA damage. Dasatinib also caused the downregulation of cancer stemness factors, including c-Myc, OCT4, and the Notch intracellular domain, as well as the decrease of phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3). The treatment of C188-9, a STAT3 inhibitor, also sensitized 231-RR cells toward radiotherapy along with the increased p-γH2Axser139, but without changing the phosphorylation of Src, indicating that STAT3 is a downstream event of Src activation. In conclusion, our data suggests that the inhibitors of Src or STAT3 could function as radiosensitizers or CSC targeting agents for TNBC radiotherapy.