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.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 36

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

×

Figure 4

DP103 is an essential regulator of NF-κB signaling.

Options: View larger image (or click on image) Download as PowerPoint
DP103 is an essential regulator of NF-κB signaling. (A) Control siRNA–tr...
(A) Control siRNA–treated (ctsi) and siDP103-treated MDA-MB-231 cells transfected with Renilla and luciferase reporter plasmid containing NF-κB or AP-1. Luciferase activity normalized and quantified. Results are average of 3 separate experiments. *P < 0.05. Control siRNA–treated (ctsi) and siDP103-treated MDA-MB-231 cells transfected with Renilla and luciferase reporter plasmid driven by NF-κB–binding sites. Cells were stimulated with (B) 10 μM VP16, (C) 25 μM doxorubicin, (D) or 10 μM CPT for 0, 6, and 12 hours and harvested for luciferase assays. Results are the average of 3 separate experiments. *P < 0.05. (E) MDA-MB-231 and BT549 cells transfected with either control siRNA (ctsi) or siDP103. Cells were left either untreated (–) or treated with CPT (10 μM), doxorubicin (10 μM), or VP16 (10 μM) for 2 hours. Protein extracts were analyzed by EMSA (top panel) and Western blotting using DP103 and GAPDH antibodies (bottom panel). (F) MDA-MB-231 cells infected either with lentiviral empty vector (lanes 1–3) or pBOBI-DP103 (lanes 4–6) were either left untreated or treated with CPT (10 μM) for indicated times. Protein extracts analyzed by EMSA and Western blotting using anti-DP103 and anti–β-actin antibodies (top panel). (G) MDA-MB-231 cells transfected with either control siRNA (ctsi) or siRNA against DP103 and subjected to CPT (10 μM) stimulation at the indicated times. Cells were harvested and lysates evaluated by Western blotting for the indicated proteins. Fold difference in protein DNA binding indicated in E and F for EMSA and for protein expression changes indicated in G for Western blot.