Regulation of Survival by IKKe in Inflammatory Breast Cancer Involves EpCAM
Technical Report,01 Dec 2012,30 Nov 2015
Dana-Farber Cancer Institute Boston United States
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Although triple negative breast cancers TNBC consistently lack hormone receptor expression and ERBB2 amplification, several lines of evidence suggest that these cancers are heterogeneous. Here we find that aberrant expression of the IkB kinase IKK related-kinase IKK drives a specific subset of TNBC and are maintained by an autocrine cytokine circuit involving JAKSTAT pathway activation. We identify CYT387 as a novel potent inhibitor of IKK and JAK signaling that disrupts this circuit and preferentially impairs the proliferation of IKK-driven breast cancer cells in vitro. CYT387 treatment inhibits both NF-kB and STAT activation and disrupts expression ofthe pro-tumorigenic cytokines CCL5 and IL-6 in these breast cancer cells. When CYT387 is combined with MEK inhibition, mouse models of triple negative breast cancer TNBC are effectively treated. As CYT387 and MEK inhibitors are already in advanced human clinical trials, this combination therapy has the potential to make apositive impact on patients suffering from TNBC.