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    DEAD-box helicase DP103 defines metastatic potential of human breast cancers

    Access Status
    Open access via publisher
    Authors
    Shin, E.
    Hay, H.
    Lee, M.
    Goh, J.
    Tan, T.
    Sen, Y.
    Lim, S.
    Yousef, E.
    Ong, H.
    Thike, A.
    Kong, X.
    Wu, Z.
    Mendoz, E.
    Sun, W.
    Salto-Tellez, M.
    Lim, C.
    Lobie, P.
    Lim, Y.
    Yap, C.
    Zeng, Q.
    Sethi, G.
    Lee, M.
    Tan, P.
    Goh, B.
    Miller, L.
    Thiery, J.
    Zhu, T.
    Gaboury, L.
    Tan, P.
    Hui, K.
    Yip, G.
    Miyamoto, S.
    Kumar, Alan Prem
    Tergaonkar, V.
    Date
    2014
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Shin, E. and Hay, H. and Lee, M. and Goh, J. and Tan, T. and Sen, Y. and Lim, S. et al. 2014. DEAD-box helicase DP103 defines metastatic potential of human breast cancers. Journal of Clinical Investigation. 124 (9): pp. 3807-3824.
    Source Title
    Journal of Clinical Investigation
    DOI
    10.1172/JCI73451
    ISSN
    0021-9738
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/51066
    Collection
    • Curtin Research Publications
    Abstract

    Despite advancement in breast cancer treatment, 30% of patients with early breast cancers experience relapse with distant metastasis. It is a challenge to identify patients at risk for relapse; therefore, the identification of markers and therapeutic targets for metastatic breast cancers is imperative. Here, we identified DP103 as a biomarker and metastasis-driving oncogene in human breast cancers and determined that DP103 elevates matrix metallopeptidase 9 (MMP9) levels, which are associated with metastasis and invasion through activation of NF-κB. In turn, NF-κB signaling positively activated DP103 expression. Furthermore, DP103 enhanced TGF-β–activated kinase-1 (TAK1) phosphorylation of NF-κB–activating IκB kinase 2 (IKK2), leading to increased NF-κB activity. Reduction of DP103 expression in invasive breast cancer cells reduced phosphorylation of IKK2, abrogated NF-κB–mediated MMP9 expression, and impeded metastasis in a murine xenograft model. In breast cancer patient tissues, elevated levels of DP103 correlated with enhanced MMP9, reduced overall survival, and reduced survival after relapse. Together, these data indicate that a positive DP103/NF-κB feedback loop promotes constitutive NF-κB activation in invasive breast cancers and activation of this pathway is linked to cancer progression and the acquisition of chemotherapy resistance. Furthermore, our results suggest that DP103 has potential as a therapeutic target for breast cancer treatment.

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