Yifan Zhu

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (3)24.16 Total impact

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    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. Implications: The CBM complex bridges key signaling pathways to confer malignant phenotypes and metastatic potential in HER2-associated breast cancer.
    No preview · Article · Sep 2015 · Molecular Cancer Research
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with a high proliferation rate. However, the molecular and genetic features that drive the aggressive clinical behavior of DLBCL are not fully defined. Here, we have demonstrated that activated Jun signaling is a frequent event in DLBCL that promotes dissemination of malignant cells. Down-regulation of Jun dramatically reduces lymphoma cell adhesion to extracellular matrix proteins, subcutaneous tumor size in nude mice, and invasive behavior, including bone marrow infiltration and interaction with bone marrow stromal cells. Furthermore, using a combination of RNA interference and gene expression profiling, we identified Jun target genes that are associated with disseminated lymphoma. Among them, ITGAV, FoxC1 and CX3CR1 are significantly enriched in patients with two or more extranodal sites. Our results point to activated Jun signaling as a major driver of the aggressive phenotype of DLBCL. Copyright © 2014 American Society of Hematology.
    No preview · Article · Dec 2014 · Blood
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    ABSTRACT: EGF activates NF-κB, and constitutively activated NF-κB contributes to EGFR mutation-associated tumorigenesis, but it remains unclear precisely how EGFR signaling leads to NF-κB activation. Here we report that CARMA3, a caspase recruitment domain (CARD)-containing scaffold molecule, is required for EGF-induced NF-κB activation. CARMA3 deficiency impaired the activation of the IKK complex following EGF stimulation, resulting in a defect of EGF-induced IκBα phosphorylation and NF-κB activation. We found that CARMA3 and Bcl10 contributed to several characteristics of EGFR-associated malignancy, including proliferation, survival, migration, and invasion. Most importantly, CARMA3 contributed to tumor growth in vivo. Our findings elucidate a crucial link between EGFR-proximal signaling components and the downstream IKK complex, and they suggest a new therapeutic target for treatment of EGFR-driven cancers.
    Full-text · Article · Mar 2011 · Cancer Research