Chronic inflammation promotes cancer progression by affecting the tumor cells and their microenvironment. Here, we demonstrate that a continuous stimulation (~6 weeks) of triple-negative breast tumor cells (TNBC) by the proinflammatory cytokines tumor necrosis factor α (TNFα) + interleukin 1β (IL-1β) changed the expression of hundreds of genes, skewing the cells towards a proinflammatory phenotype. While not affecting stemness, the continuous TNFα + IL-1β stimulation has increased tumor cell dispersion and has induced a hybrid metabolic phenotype in TNBC cells; this phenotype was indicated by a transcription-independent elevation in glycolytic activity and by increased mitochondrial respiratory potential (OXPHOS) of TNBC cells, accompanied by elevated transcription of mitochondria-encoded OXPHOS genes and of active mitochondria area. The continuous TNFα + IL-1β stimulation has promoted in a glycolysis-dependent manner the activation of p65 (NF-kB), and the transcription and protein expression of the prometastatic and proinflammatory mediators sICAM-1, CCL2, CXCL8 and CXCL1. Moreover, when TNBC cells were stimulated continuously by TNFα + IL-1β in the presence of a glycolysis inhibitor, their conditioned media had reduced ability to recruit monocytes and neutrophils in vivo. Such inflammation-induced metabolic plasticity, which promotes prometastatic cascades in TNBC, may have important clinical implications in treatment of TNBC patients.

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