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

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

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 1

DP103 levels correlate with invasiveness and malignancy.

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DP103 levels correlate with invasiveness and malignancy. DP103 staining ...
DP103 staining of (A) normal ductal tissue and (B) an IDC. (C) Gene expression value of DP103 (y axis) plotted for each breast cancer subtype, namely basal, claudin-low, luminal-A, luminal-B, ERBB2 (HER2+), and normal-like. (D) Kaplan-Meier curves showing DP103 expression in relation to patients’ OS. Cases that have not experienced a positive event are censored at the date of last follow-up (small vertical lines on the line plots). (E) Kaplan-Meier curves showing DP103 expression in relation to SAR. Cases that have not experienced a positive event are censored at the date of last follow-up (small vertical lines on the line plots). (F) Breast cancer progression model showing isogenic cell lines with increasing invasive potential. (G) Western blotting with DP103 antibody in lysates from the isogenic cell lines (F). (H) qPCR with DP103 mRNA expression in RNA from the isogenic cell lines (F). (I) Gene expression of DP103 correlates with breast metastasis activity by Spearman correlation (64). Red dotted line is curve fitted by linear regression. (J) Primary breast tissues from patients with benign disease, no lymph node metastases (Non-Met), and lymph node metastases (Met) collected and analyzed for DP103 mRNA expression **P < 0.01; ***P < 0.001. (K) RNA from breast cell lines and qPCR performed with DP103 primers. (L) Protein from breast cell lines extracted and levels of DP103 protein evaluated. Fold difference in protein expression indicated in G and L.