CBM Complex in Breast Cancer

The HER2/Neu protein is overexpressed in a large fraction of human breast cancers. NF-B is one of several transcription factors that are aberrantly activated in HER2-positive breast cancers; however, the molecular mechanism by which HER2 activates NF-B remains unclear. The CARMA3–BCL10–MALT1 (CBM) complex is required for GPCR- and EGFR-induced NF-B activation. In the current study, the role of the CBM complex in HER2-mediated NF-B activation and HER2-positive breast cancer was investigated. Interestingly, HER2-mediated NF-B 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-B activation and functionally contributes to multiple properties of malignancy, such as proliferation, avoidance of apoptosis, migration, and invasion, both in vitro and in vivo. In addition, CARMA3-mediated NF-B 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-B activation in HER2-positive breast cancer progression, Malt1 knockout mice (Malt1–/–) 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 Malt1 knockout mice compared with control mice. In summary, the...

Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Pan, D., Zhu, Y., Zhou, Z., Wang, T., You, H., Jiang, C., Lin, X. Tags: Signal Transduction Source Type: research