The IL-8/NF-κB feedback loop confers a paclitaxel-sensitive/doxorubicin-resistant phenotype in triple-negative breast...

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is highly metastatic compared with other BC subtypes. Taxane- and anthracycline-based therapies remain the main clinical TNBC regimens. However, TNBC patients usually suffer through chemotherapy owing to the lack of valid biomarkers to predict therapeutic effectiveness. We found that IL-8 upregulation is detected in paclitaxel (PTX)-sensitive/doxorubicin (DOX)-resistant TNBC cells. Moreover, transcriptional profiling revealed that, compared with non-TNBC and normal mammary tissues, TNBC tissues highly express IL-8; its upregulation predicted a favorable response to taxane treatment but poor sensitivity to anthracycline-based therapy in TNBC cohorts. Whereas IL-8 supplementation in HCC1937 cells, which exhibit lower IL-8 expression and a PTX-resistant/DOX-sensitive phenotype, enhanced the cellular response to PTX but reduced their sensitivity to DOX, IL-8 knockdown in Hs578t cells, which have higher IL-8 expression and a PTX-sensitive/DOX-resistant phenotype, desensitized those cells to PTX treatment but improved their sensitivity to DOX. Gene set enrichment analysis (GSEA) results indicated that IL-8 upregulation is likely associated with E2F-regulated cell cycle progression and the activation of the NF-kB and MTOC1 pathways in TNBC. IL-8 supplementation promoted but IL-8 knockdown in Hs578t cells suppressed the activity of the E2F, NF-kB and MTOC1 signaling pathways. Immunohistochemistry (IHC) revealed that higher and lower IL-8/p-NF-κB protein levels predicted good therapeutic outcomes in TNBC patients who initially received taxane and anthracycline-based chemotherapy, respectively. This study revealed that the formation of an IL-8/NF-kB feedback loop is required for maintaining the PTX-sensitive/DOX-resistant phenotype in TNBC.