Pleiotropic roles of AEG-1/MTDH/LYRIC in breast cancer

Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Advances in Cancer Research (Impact Factor: 5.32). 12/2013; 120:113-34. DOI: 10.1016/B978-0-12-401676-7.00004-8
Source: PubMed


Since the initial discovery of AEG-1/MTDH/LYRIC, our appreciation for this novel protein's involvement in cancer has increased dramatically over the past few years. AEG-1/MTDH/LYRIC is a key functional target of the 8q22 genomic gain that is frequently observed in poor-prognosis breast cancer, where it plays a dual role in promoting chemoresistance and metastasis. Beyond this, growing evidence from clinical research indicates a strong correlation between AEG-1/MTDH/LYRIC expression and the pathogenesis of a large spectrum of cancer types, and multiple studies employing in vitro cell culture systems and in vivo xenograft models have revealed multifaceted roles of AEG-1/MTDH/LYRIC in cancer biology, including tumor cell proliferation, apoptosis, angiogenesis, and autophagy. With increasing mechanistic understanding of AEG-1/MTDH/LYRIC, discovery of agents that can block AEG-1/MTDH/LYRIC and its regulated pathways will be beneficial to cancer patients with aberrant expression of AEG-1/MTDH/LYRIC.

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    • "INTRODUCTION MTDH, also known as metadherin, is overexpressed in a large spectrum of cancer types, and its elevated levels are associated with poor prognosis in cancer patients (Sarkar and Fisher, 2013; Wan and Kang, 2013). Functionally, MTDH has been implicated in several cancer-related processes, including proliferation, cell death, invasion, and angiogenesis, and has been linked to multiple oncogenic pathways such as PI3K/AKT, Wnt/b-catenin, and NF-kB (Emdad et al., 2013; Wan and Kang, 2013). "
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    ABSTRACT: Metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) are overexpressed and interact in diverse cancer types. The structural mechanism of their interaction remains unclear. Here, we determined the high-resolution crystal structure of MTDH-SND1 complex, which reveals an 11-residue MTDH peptide motif occupying an extended protein groove between two SN domains (SN1/2), with two MTDH tryptophan residues nestled into two well-defined pockets in SND1. At the opposite side of the MTDH-SND1 binding interface, SND1 possesses long protruding arms and deep surface valleys that are prone to binding with other partners. Despite the simple binding mode, interactions at both tryptophan-binding pockets are important for MTDH and SND1's roles in breast cancer and for SND1 stability under stress. Our study reveals a unique mode of interaction with SN domains that dictates cancer-promoting activity and provides a structural basis for mechanistic understanding of MTDH-SND1-mediated signaling and for exploring therapeutic targeting of this complex.
    Cell Reports 09/2014; 8(6). DOI:10.1016/j.celrep.2014.08.033 · 8.36 Impact Factor
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    • "The study discovered nine novel variants and found two variants to be associated with the susceptibility of breast cancer. AEG-1/MTDH has a dual function in promoting chemoresistance and metastasis, and is a key functional target of the 8q22 genomic gain that is frequently observed in breast cancer patients with a poor prognosis (62). In summary, AEG-1/MTDH overexpression contributes to an aggressive phenotype, leading to a poor prognosis in primary invasive breast cancer. "
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    ABSTRACT: Tumor development is initiated by an accumulation of numerous genetic and epigenetic alterations that promote tumor initiation, invasion and metastasis. Astrocyte elevated gene-1 [AEG-1; also known as Metadherin (MTDH) and Lysine-rich CEACAM1 co-isolated (LYRIC)] has emerged in recent years as a potentially crucial mediator of tumor malignancy, and a key converging point of a complex network of oncogenic signaling pathways. AEG-1/MTDH has a multifunctional role in tumor development that has been found to be involved in the following signaling cascades: i) The Ha-Ras and PI3K/Akt pathways; ii) the nuclear factor-κB signaling pathway; iii) the ERK/mitogen-activated protein kinase and Wnt/β-catenin pathways; and iv) the Aurora-A kinase signaling pathway. Studies have established that AEG-1/MTDH is crucial in tumor progression, including transformation, the evasion of apoptosis, invasion, angiogenesis and metastasis. In addition, recent clinical studies have convincingly associated AEG-1/MTDH with tumor progression and poor prognosis in a number of cancer types, including hepatocellular, esophageal squamous cell, gallbladder and renal cell carcinomas, breast, non-small cell lung, prostate, gastric and colorectal cancers, and glioma, melanoma, neuroblastoma and osteosarcoma. AEG-1/MTDH may be used as a biomarker to identify subgroups of patients who require more intensive treatments and who are likely to benefit from AEG-1/MTDH-targeted therapies. The therapeutic targeting of AEG-1/MTDH may simultaneously block metastasis, suppress tumor growth and enhance the efficacy of chemotherapeutic treatments.
    Oncology letters 08/2014; 8(2):493-501. DOI:10.3892/ol.2014.2231 · 1.55 Impact Factor
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    ABSTRACT: Alb/MTDH: A transgenic mouse with hepatocyte-specific expression of AEG-1 by directing the expression of human AEG-1 under an upstream enhancer region fused to the 335-base-pair core region of mouse albumin promoter.
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