Abstract
NF-κB is a transcription factor involved in the regulation of multiple physiological and pathological cellular processes, including inflammation, cell survival, proliferation, and cancer cell metastasis. NF-κB is frequently hyperactivated in several cancers, including triple-negative breast cancer. Here we show that NF-κB activation in breast cancer cells depends on the presence of the CHORDC1 gene product Morgana, a previously unknown component of the IKK complex and essential for IκBα substrate recognition. Morgana silencing blocks metastasis formation in breast cancer mouse models and this phenotype is reverted by IκBα downregulation. High Morgana expression levels in cancer cells decrease recruitment of natural killer cells in the first phases of tumor growth and induce the expression of cytokines able to attract neutrophils in the primary tumor, as well as in the pre-metastatic lungs, fueling cancer metastasis. In accordance, high Morgana levels positively correlate with NF-κB target gene expression and poor prognosis in human patients.
Highlights
NF-κB is a transcription factor involved in the regulation of multiple physiological and pathological cellular processes, including inflammation, cell survival, proliferation, and cancer cell metastasis
We recently demonstrated that Morgana is frequently overexpressed in triple-negative breast cancer (TNBC) and its expression correlates with lymph node positivity[14]
Morgana is expressed at higher levels in MDA-MB-231 and BT549 TNBC cell lines compared to noninvasive MCF7 cancer cells and MCF10A normal breast cells (Fig. 1a)
Summary
NF-κB is a transcription factor involved in the regulation of multiple physiological and pathological cellular processes, including inflammation, cell survival, proliferation, and cancer cell metastasis. In the TNBC cell line BT549, unable to form metastasis in vivo, the role of Morgana in invasion has been confirmed through its downregulation and overexpression followed by in vitro invasion assays (Supplementary Fig. 1c). In an in vitro IKKβ kinase assay the phosphorylation of a recombinant IκBα substrate was significantly impaired in Morgana downregulated cells compared to controls (Fig. 4k).
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