Tumor Necrosis Factor-alpha Induces Interleukin-6 Production Via Extracellular-regulated Kinase 1 Activation in Breast Cancer Cells

Interleukin-6 (IL-6) and interleukin-11 (IL-11) are frequently produced by breast cancer cells. These interleukins promote osteoclast formation and may mediate osteolysis at the site of breast cancer bone metastases. Transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) up-regulate IL-6 and IL-11 production in a cytokine-dependent fashion in breast cancer cells, but very little is known about their intracellular signaling pathways in breast cancer cells. To study TGF-beta, TNF-alpha and IL-1beta regulation of IL-6 and IL-11 production in human MDA-MB-231 breast cancer cells, we established single cell clones stably expressing dominant negative (DN) forms of the mitogen-activated protein kinases p38 (p38/AF) or ERK1 (ERK1K71R). We show here, that while basal, TGF-beta and IL-1beta induced IL-6 production was similar in parental cells and in pcDNA3 control, ERK1K71R and p38/AF clones, TNF-alpha induced IL-6 production was blunted in the ERK1K71R clones. TGF-beta and IL-1beta, but not TNF-alpha, induced IL-11 production in parental MDA-MB-231 cells. Similar findings were detected in clones stably expressing p38/AF and ERK1K71R, which did not change basal IL-11 production either. In conclusion, TNF-alpha induced IL-6 production is mediated via ERK1 activation in MDA-MB-231 cells. These observations may be helpful in designing new anti-osteolytic therapies.