MTDH Activation by 8q22 Genomic Gain Promotes Chemoresistance and Metastasis of Poor-Prognosis Breast Cancer

Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Cancer cell (Impact Factor: 23.52). 02/2009; 15(1):9-20. DOI: 10.1016/j.ccr.2008.11.013
Source: PubMed


Targeted therapy for metastatic diseases relies on the identification of functionally important metastasis genes from a large number of random genetic alterations. Here we use a computational algorithm to map minimal recurrent genomic alterations associated with poor-prognosis breast cancer. 8q22 genomic gain was identified by this approach and validated in an extensive collection of breast tumor samples. Regional gain of 8q22 elevates expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers and is associated with poor clinical outcomes. Functional characterization of MTDH revealed its dual role in promoting metastatic seeding and enhancing chemoresistance. These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk.

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    • "MTDH is an oncogene that plays a dual role in promoting BrCa proliferation and enhancing chemoresistance. It has been found to be overexpressed in over 40% of breast cancers and is considered as an important target for exploration of cancer therapy [41]. qPCR results (Fig. 10) revealed that different ratios of MSCs and Fig. 5. Improved MDA-MB-231 cell proliferation in the 10% nHA/chitosan bone scaffolds for 1, 3 and 5 days. "
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    ABSTRACT: Traditional breast cancer (BrCa) bone metastasis models contain many limitations with regards to controllability, reproducibility, and flexibility of design. In this study, a novel biomimetic bone microenvironment was created by integrating hydroxyapatite (HA) and native bioactive factors deposited by osteogenic induction of human bone marrow mesenchymal stem cells (MSCs) within a cytocompatible chitosan hydrogel. It was found that a 10% nanocrystalline HA (nHA) chitosan scaffold exhibited the highest BrCa adhesion and proliferation when compared to chitosan scaffolds with 20% nHA, 10% and 20% microcrystalline HA as well as amorphous HA. This 3D tunable bone scaffold can provide a biologically relevant environment, increase cell-cell and cell-matrix interactions as found in native bone, and retain the behavior of BrCa cells with different metastasis potential (i.e., highly metastatic MDA-MB-231, less metastatic MCF-7 and transfected MDA-MB-231). The co-culture of MSCs and MDA-MB-231 in this bone model illustrated that MSCs have the capacity to upregulate the expression of the well-known metastasis-associated gene metadherin within BrCa cells. In summary, this study illustrates the capacity of our 3D bone model in creating a biomimetic environment conducive to recapitulating the behavior of metastatic BrCa cells, making it a promising tool for in vitro BrCa cell bone metastasis study and potential therapeutics discovery. Copyright © 2014. Published by Elsevier Ltd.
    Full-text · Article · Dec 2014 · Acta Biomaterialia
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    • "One of the important hallmarks of aggressive cancers is chemoresistance. Previous studies have suggested that AEG-1/MTDH contributes to a broad spectrum of resistance to various chemotherapeutics, including 5-fluorouracil, doxorubicin, paclitaxel, cisplatin and 4-hydroxycyclophosphamide (16,46–48). In human HCC cells, the gene expression profiles of overexpressed AEG-1/MTDH have been identified in several drug-metabolizing enzymes involved in chemoresistance, including dihydropyrimidine dehydrogenase, cytochrome P450B6, dihydrodiol dehydrogenase, ATP-binding cassette transporter 11/MRP8 and transcription factor LSF/TFCP2 (15). "
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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.
    Full-text · Article · Aug 2014 · Oncology letters
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    • "Recently, MTDH has become considered an important molecule in the modulation of cell proliferation, angiogenesis, drug resistance, and stem cell transformation32. Its overexpression is observed in a number of malignancies, including HCC, breast cancer, malignant glioma, and neuroblastoma, and is associated with poor clinical outcome17183334. MTDH has been proven to promote the motility of cancer cells161718. "
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    ABSTRACT: Endothelial cells (ECs) are critical for angiogenesis, and microRNA plays important roles in this process. In this study, we investigated the function and mechanism of miR-302c in the process of endothelial-mesenchymal transition (EndMT) in ECs. When miR-302c was overexpressed in HUVECs, the motility of the HUVECs was weakened; the expression levels of EndMT markers were also changed: vascular endothelial (VE)-cadherin was up-regulated, whereas β-catenin, FSP1, and α-SMA were down-regulated. Further in vivo and in vitro experiments showed that the growth of HCC was inhibited when co-cultured or co-injected with HUVECs overexpressing miR-302c. On the contrary, when miR-302c was suppressed in HUVECs, the opposite results were observed. Reporter assays showed that miR-302c inhibited metadherin (MTDH) expression through directly binding to its 3'UTR. In addition, compared to ECs isolated from normal liver tissues of HCC patients, ECs isolated from tumor tissues expressed markedly low levels of miR-302c but high levels of MTDH. These results suggest that EC-specific miR-302c suppresses tumor growth in HCC through MTDH-mediated inhibition of EndMT. MTDH and miR-302c might provide a new strategy for anti-angiogenic therapy in HCC.
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