title: The CBM Complex Underwrites NF-κB Activation to Promote HER2-Associated Tumor Malignancy.
abstract: 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 in vitro and in vivo. 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, 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, 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.
  
  
  CONCLUSIONS
  The CBM complex bridges key signaling pathways to confer malignant phenotypes and metastatic potential in HER2-associated breast cancer.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: Deng
authors.initials: D
authors.lastname: Pan
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Harrison
authors.initials: H
authors.lastname: You
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Changying
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas. xllin@mdanderson.org.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D020169:Caspases; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C118591:BCL10 protein, human; C430880:CARD10 protein, human; C508053:ERBB2 protein, human; C400109:MALT1 protein, human