Integrin-linked kinase as a novel molecular switch of the IL-6-NF-κB signaling loop in breast cancer

IL-6-NF-kappa B signaling is linked to aggressive cancer phenotypes. We report a previously unknown function of integrin-linked kinase (ILK) as a critical mediator of IL-6-NF-kappa B signaling in breast cancer cells, which provides a rationale for exploiting ILK inhibition as a therapeutic strategy.Substantial evidence has clearly demonstrated the role of the IL-6-NF-kappa B signaling loop in promoting aggressive phenotypes in breast cancer. However, the exact mechanism by which this inflammatory loop is regulated remains to be defined. Here, we report that integrin-linked kinase (ILK) acts as a molecular switch for this feedback loop. Specifically, we show that IL-6 induces ILK expression via E2F1 upregulation, which, in turn, activates NF-kappa B signaling to facilitate IL-6 production. shRNA-mediated knockdown or pharmacological inhibition of ILK disrupted this IL-6-NF-kappa B signaling loop, and blocked IL-6-induced cancer stem cells in vitro and estrogen-independent tumor growth in vivo. Together, these findings establish ILK as an intermediary effector of the IL-6-NF-kappa B feedback loop and a promising therapeutic target for breast cancer.