Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine with known multiple functions in immune regulation, inflammation, and oncogenesis. Binding of IL-6 to the IL-6 receptor (IL-6R) induces homodimerization and recruitment of glycoprotein 130 (gp130), which leads to activation of downstream signaling. Emerging evidence suggests that high levels of IL-6 are correlated with poor prognosis in breast cancer patients. IL-6 appears to play a critical role in the growth and metastasis of breast cancer cells, renewal of breast cancer stem cells (BCSCs), and drug resistance of BCSCs, making anti–IL-6/IL-6R/gp130 therapies promising options for the treatment and prevention of breast cancers. However, preclinical and clinical studies of the applications of anti–IL-6/IL-6R/gp130 therapy in breast cancers are limited. In this review, we summarize the structures, preclinical and clinical studies, mechanisms of action of chemical and biological blockers that directly bind to IL-6, IL-6R, or gp130, and the potential clinical applications of these pharmacological agents as breast cancer therapies.
Highlights
Recent studies have demonstrated that the proinflammatory cytokine interleukin-6 (IL-6) plays an important role in tumor progression and metastasis [115]
An alternative to classicsignaling has recently been described, termed transsignaling, in which a complex is formed between IL-6 and a soluble form of IL-6 receptor (IL-6R), sIL-6R, which joining with membrane gp130 to generate downstream signaling events [19] (Figure 1)
Evidence of direct interaction www.impactjournals.com/oncotarget between SC144 and gp130 was provided by drug affinity responsive target stability (DARTS) assay [94], and to date, no preclinical or clinical data are available for breast cancer therapy
Summary
Recent studies have demonstrated that the proinflammatory cytokine interleukin-6 (IL-6) plays an important role in tumor progression and metastasis [115]. Studies have shown that inhibition of IL-6 expression by shRNA in triplenegative breast cancer cells can lead to the suppression of colony formation and decreased cell survival in vitro as well as decreased tumor engraftment and growth in vivo [40]. Utilizing IL-6 signaling inhibitors to target the tumor microenvironment and indirectly block cancer cell growth could be effective in treating and preventing breast carcinogenesis.
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