Journal
MOLECULAR CELL
Volume 45, Issue 6, Pages 777-789Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2012.01.015
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Funding
- United States Department of Defense [W81XWH-09-1-0533]
- National Institutes of Health [1R01CA140956-01]
- Florida Department of Health [09BB-13]
- Frenchman's Creek Women For Cancer Research
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Abnormal inflammatory signaling activation occurs commonly in cancer cells. However, how it is initiated and maintained and its roles in early stages of tumor-igensis 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-kappa B 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.
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