RANKL Promotes Chemotherapy Resistance in Breast Cancer Cells Through STAT3 Mediated Autophagy Induction

This study was to investigate the functional role and mechanism of receptor activator of nuclear factor-kappa B ligand (RANKL) associated autophagy and chemoresistance in breast cancer.Cell Counting Kit-8 (CCK-8) assay was used to detect the cell viability. Real-time polymerase chain reaction (PCR) was used for determining the relative mRNA levels of key genes and protein expression was assessed by Western blotting. Immunofluorescence was performed to evaluate the changes in the autophagy flux. Short hairpin (shRNA) was used to knockdown the expression of the target genes in breast cancer cells. Based on The Cancer Genome Atlas (TCGA) database, we explored the expression of receptor activator of nuclear factor-kappa B (RANK), autophagy and signal transducer and activator of transcription 3 (STAT3) signaling associated genes and analyzed their correlation with the prognosis of breast cancer patients.The findings showed that receptor activator of nuclear factor-kappa B ligand (RANKL), the ligand of RANK, could effectively enhance the chemoresistance potential of breast cancer cells. Our results showed that RANKL induced autophagy and enhanced the expression of autophagy associated genes in breast cancer cells. The knockdown of RANK suppressed RANKL mediated autophagy induction in these cells. Furthermore, the inhibition of autophagy suppressed RANKL mediated chemoresistance in breast cancer cells. We found STAT3 signaling pathway was involved in RANKL-induced autophagy. Analysis of the expression of RANK, and autophagy and STAT3 signaling associated genes in breast cancer tissues showed that the expression of autophagy and STAT3 signaling associated genes was correlated with the prognosis of breast cancer patients.The present study suggests that the RANKL/RANK axis may potentially mediate chemoresistance in breast cancer cells by inducing autophagy through the STAT3 signaling pathway.