Data from The CBM Complex Underwrites NF-κB Activation to Promote HER2-Associated Tumor Malignancy

Abstract

<div>Abstract<p>The HER2/Neu protein is overexpressed in a large fraction of human breast cancers. NF-κB is one of several transcription factors that are aberrantly activated in HER2-positive breast cancers; however, the molecular mechanism by which HER2 activates NF-κB remains unclear. The CARMA3–BCL10–MALT1 (CBM) complex is required for GPCR- and EGFR-induced NF-κB activation. In the current study, the role of the CBM complex in HER2-mediated NF-κB activation and HER2-positive breast cancer was investigated. Interestingly, HER2-mediated NF-κB activation requires protein kinase C (PKC) activity rather than AKT activity. Using biochemical and genetic approaches, it was shown that the CBM complex is required for HER2-induced NF-κB activation and functionally contributes to multiple properties of malignancy, such as proliferation, avoidance of apoptosis, migration, and invasion, both <i>in vitro</i> and <i>in vivo</i>. In addition, CARMA3-mediated NF-κB activity was required for the upregulation of two matrix metalloproteinases (MMP), MMP1 and MMP13, both of which contribute to tumor metastasis. To further access the physiologic role of CBM complex-mediated NF-κB activation in HER2-positive breast cancer progression, <i>Malt1</i> knockout mice (<i>Malt1</i><sup>−/−</sup>) were crossed with MMTV-Neu mice, in which mammary tumors spontaneously developed with HER2 overexpression. We observed delayed onset and prolonged progression time in mammary tumors in <i>Malt1</i> knockout mice compared with control mice. In summary, these data demonstrate that the CBM complex is a crucial component mediating HER2-induced NF-κB signaling and tumor malignancy in HER2-positive breast cancer.</p><p><b>Implications:</b> The CBM complex bridges key signaling pathways to confer malignant phenotypes and metastatic potential in HER2-associated breast cancer. <i>Mol Cancer Res; 14(1); 93–102. ©2015 AACR</i>.</p></div>