Tumor Necrosis Factor-α Induces Interleukin-6 Production via Extracellular-Regulated Kinase 1 Activation in Breast Cancer Cells

Abstract

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.

Zoledronic-Acid-Induced Circulating Level Modifications of Angiogenic Factors, Metalloproteinases and Proinflammatory Cytokines in Metastatic Breast Cancer Patients

“…Comparing the day 7 values with the day 2 ones after ZA infusion, our linear regression model showed a significantpositive correlation between IL-6 and TNF-α. It has recently been reported that TNF-α induces IL-6 production via extracellular-regulated kinase 1 activation in breast cancer cells [21]. Concerning the possible influence of exemestane by itself on IL-6 serum levels, a statistically not significant difference between median IL-6 values at baseline and at 8 weeks of therapy with exemestane has recently been reported in postmenopausal breast cancer women failing on nonsteroidal aromatase inhibitors and not receiving ZA [22].…”

Tamoxifen Resistant Breast Cancer and Autophagy

“…Currently it is not known if chemo-resistant niches are present in other cancers or if tamoxifen can elicit the development of such niches. Notwithstanding, in breast cancer cells, tumor necrosis factor alpha (TNFα) can induce the expression of IL-6 along with IL-11, promoting osteoclast formation and mediating osteolysis at the site of breast cancer bone metastases (Suarez-Cuervo et al, 2003). IL-6 has also been implicated in mediating oncogene-induced cellular senescence (Kuilman et al, 2008).…”

Breast Cancer Progression: A “Vicious Cycle” of Pro-Malignancy Activities is Mediated by Inflammatory Cells, Chemokines and Cytokines

“…As indicated in the IL-1 section, associations and additive effects between the two cytokines were shown (164,175,177), suggesting that interactions between them may support the malignancy process in breast cancer. Positive feedback loop between IL-6 and TNFα may also exist, as TNFα induced up-regulation of IL-6 in human and murine breast cancer cells (83,153,175).…”

“…Some of these activities were mentioned above, consisting of interactions between IL-1 and the pro-malignancy chemokines CXCL8 and CCL2. IL-1α and IL-1β may also increase the expression and activities of other inflammatory and potentially pro-malignancy cytokines, TNFα and IL-6, by breast tumor cells and/or fibroblasts (153,172,175,176). The associations between IL-1 and IL-6 were further validated by the correlation between IL-1α and IL-6 expression noted in breast tumor biopsies (164), and also by the fact that IL-1 additively acted with IL-6 to induce breast cancer motility and spreading (177).…”

“…Cross-interactions may also exist between one inflammatory cytokine and other such cytokines, as suggested by the fact that TNFα increased in breast tumor cells the secretion of the inflammatory cytokine IL-6 (83,175), and synergised with IL-1β in tumor-promoting activities (178). Further positive feedback events between the different inflammatory cytokines may be mediated by IL-1α-induced elevation of TNFα expression by breast cancer cells (172,176).…”