IL6-Mediated Suppression of miR-200c Directs Constitutive Activation of Inflammatory Signaling Circuit Driving Transformation and Tumorigenesis

Abstract

Abnormal inflammatory signaling activation occurs commonly in cancer cells. However, how it is initiated and maintained and its roles in early stages of tumorigensis are largely unknown. Here, we report that the monocyte-derived MCP-1-induced transformation of immortal breast epithelial cells is triggered by transient activation of MEK/ERK and IKK/NF-κB pathways and maintained by constitutive activation of a feed-forward inflammatory signaling circuit composed of miR-200c, p65, JNK2, HSF1, and IL6. Suppression of miR-200c by IL6 constitutively activates p65/RelA and JNK2, and the latter phosphorylates and activates HSF1. In turn, HSF1 triggers demethylation of the IL6 promoter that facilitates the binding of p65 and c-Jun, which together drive constitutive IL6 transcription. Importantly, this signaling circuit is manifest in human cancer cells and in a mouse model of ErbB2-driven breast cancer, where IL6 loss significantly impairs tumorigenesis. Therefore, targeting this signaling circuit represents an effective therapeutic avenue for breast cancer prevention and treatment.