Iron promotes breast cancer cell migration via IL-6/JAK2/STAT3 signaling pathways in a paracrine or autocrine IL-6-rich inflammatory environment

Abstract

Iron overload can act as catalyst for the formation of free radicals, which may promote oxidant-mediated breast carcinogenesis. However, the association between iron and breast cancer has not been comprehensively elucidated. In this study, we found that iron overload upregulated the inflammatory cytokine interleukin-6 (IL-6) expression to activate Janus Kinases 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling in triple negative breast cancer (TNBC) MDA-MB-231 cell lines, resulting in epithelial-mesenchymal transition (EMT) and cancer cell migration, but it had no effects on the estrogen receptor (ER)-positive breast cancer MCF-7 cells. However, in the presence of exogenous IL-6, iron overload could also dramatically induce an autocrine IL-6 loop in ER-positive MCF-7 cells to active IL-6/JAK2/STAT3 signaling, resulting in enhanced EMT and cell motility. In vivo animal studies also identified that iron overload promoted the progression of low metastatic breast cancer tumorigenicity and lung metastasis following the addition of exogenous IL-6. This study suggested that iron overload could result in inducible IL-6 expression leading to promote malignant transformation of breast cancer cells in an paracrine or autocrine IL-6-rich inflammatory environment. Anti-inflammation and iron depletion therapy would be an effective therapeutic/preventive strategy for suppressing breast cancer progression.