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DEAD-box helicase DP103 defines metastatic potential of human breast cancers
Eun Myoung Shin, … , Alan Prem Kumar, Vinay Tergaonkar
Eun Myoung Shin, … , Alan Prem Kumar, Vinay Tergaonkar
Published August 1, 2014
Citation Information: J Clin Invest. 2014;124(9):3807-3824. https://doi.org/10.1172/JCI73451.
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Research Article Oncology Article has an altmetric score of 36

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

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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.

Authors

Eun Myoung Shin, Hui Sin Hay, Moon Hee Lee, Jen Nee Goh, Tuan Zea Tan, Yin Ping Sen, See Wee Lim, Einas M. Yousef, Hooi Tin Ong, Aye Aye Thike, Xiangjun Kong, Zhengsheng Wu, Earnest Mendoz, Wei Sun, Manuel Salto-Tellez, Chwee Teck Lim, Peter E. Lobie, Yoon Pin Lim, Celestial T. Yap, Qi Zeng, Gautam Sethi, Martin B. Lee, Patrick Tan, Boon Cher Goh, Lance D. Miller, Jean Paul Thiery, Tao Zhu, Louis Gaboury, Puay Hoon Tan, Kam Man Hui, George Wai-Cheong Yip, Shigeki Miyamoto, Alan Prem Kumar, Vinay Tergaonkar

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Figure 7

DP103 is a positive cofactor of TAK1-mediated IKK2 activation in MDA-MB-231 cells.

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DP103 is a positive cofactor of TAK1-mediated IKK2 activation in MDA-MB-...
(A) Nuclear and cytoplasmic fractions immunoprecipitated with TAK1 and IgG control antibodies and immunoprecipitate material and lysates analyzed by immunoblotting with the indicated antibodies. (B) GST-TAK1 and His-DP103 incubated either separately or together. Immunoprecipitates analyzed by immunoblotting with the indicated antibodies. (C) Kinase assay performed using GST-TAK1 either with GST-IKK2-WT or GST-IKK2-Mut substrates with increasing input of His-DP103 protein. (D) Cells transfected either with control siRNA or siDP103 and stimulated with TNF-α. Lysates were immunoprecipitated using anti-TAK1 antibody, and kinase assay was performed using GST–IKK2 (amino acid residues 152–204) as substrate (top panel). (E) Cells transfected with DP103, siDP103, and respective control vectors. IKK complex immunoprecipitated with anti-NEMO antibody. IKK activity was determined using phosphorylation of IκBα. (F) Cells transfected either with control siRNA or siTAK1 and stimulated with TNF-α. Total RNA analyzed for mRNA expression of NF-κB target genes. *P < 0.05; ***P < 0.001. (G) Cells treated with IKK2 inhibitor IV or TAK1 inhibitor (5Z)-7-oxozeaenol and stimulated with TNF-α. MMP9 activity evaluated with zymography. (H) Cells treated with control siRNA (ctsi) or siRNAs against TAK1 (siTAK1) and stimulated with TNF-α. MMP9 activity evaluated with zymography. (I) Cells transfected either with control siRNA or siRNAs against TAK1. Invaded cells through Matrigel detached and lysed in assay buffer were presented as relative fluorescence units (RFU). ***P < 0.001. Fold differences in protein expression are indicated in C–E.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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