Research

DEAD-box Helicase DP103 Defines Metastatic Potential of Human Breast Cancers (J Clin Invest, Aug 2014)

Despite advancement in breast cancer treatment, 30% patients with early breast cancers experience relapse with distant metastasis. Therefore, there is a pressing need to identify new markers and therapeutic targets for metastatic breast cancers. Herein, we identify DP103 as a novel biomarker and metastasis-driving oncogene. We show that DP103’s function in breast cancers is attributable to its ability to elevate MMP9 levels through activation of NFkB. NFkB signaling in turn also positively activates DP103 expression. We further delineate that NFkB activation by DP103 depends on its function as a positive co-factor of TGFb-activated kinase-1 (TAK1) to phosphorylate IKK2, the key NFkB activating kinase. Reducing DP103 expression in invasive breast cancers reduces phosphorylation of IKK2, abrogates NFkB mediated MMP9 expression and hence impedes metastasis. Given that levels of DP103 are limiting in normal cells, the DP103-NFkB positive feedback loop explains a key mechanism of constitutive NFkB activation apparent in cancers especially since amplifications of TAK1 or IKK2 in cancers are rare. Furthermore, since DP103 promotes activation of NFkB, an oncogenic transcription factor whose hyperactivity is not only functionally linked to cancer progression, but also to acquisition of resistance to chemotherapy, our results provide a novel drug target for treatment of breast cancer.

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In summary, we describe a function of an RNA helicase DP103 that depends on its ability to bind and stabilize TAK1 and thus activate NF-κB signaling. Although constitutive activation of NF-κB is a well-documented phenomenon in cancer, increased levels of enzymes such as TAK1 that could maintain IKK2 and hence NF-κB in a constitutively active state are not seen in cancer cells. Instead, our current study uncovered that it is the increase in levels of DP103 that marks the switch from a nonmetastatic to a metastatic state in breast cancer cells and possibly other cancer cell types. In addition, we also elucidated a plausible DP103–NF-κB–positive feed-forward loop that could be involved in the maintenance of this oncogenic signaling arm in cancers. Thus, we suggest that DP103 is a novel biomarker as well as a worthwhile therapeutic drug target.

Authors:

Eun Myoung Shin1,2, Hui Sin Hay1,2,3, Moon Hee Lee4, Jen Nee Goh1,3, Tuan Zea Tan1, Yin Ping Sen5, See Wee Lim5, Einas M. Yousef6, Hooi Tin Ong7, Aye Aye Thike8, Xiangjun Kong9, Zhengsheng Wu9, Earnest Mendoz10, Wei Sun10, Manuel Salto-Tellez1,11,12, Chwee Teck Lim10,13,14, Peter E. Lobie1,3,15, Yoon Pin Lim16, Celestial T. Yap17,18, Qi Zeng2,16, Gautam Sethi1,3, Martin B. Lee19, Patrick Tan1,20,21, Boon Cher Goh1,18,22,Lance D. Miller23, Jean Paul Thiery1,2,16,18, Tao Zhu9, Louis Gaboury6, Puay Hoon Tan8, Kam Man Hui7, George Wai-Cheong Yip5, Shigeki Miyamoto4,

Alan Prem Kumar1,3,18,24,25,#, Vinay Tergaonkar2,16,#

1Cancer Science Institute of Singapore, National University of Singapore, Singapore;

2Institute of Molecular and Cellular Biology, A*Star, Singapore;

Departments of 3Pharmacology, 5Anatomy, 11Pathology, 16Biochemistry, and 17Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;

4McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Wisconsin, USA;6Institute for research in immunology and cancer (IRIC), University of Montreal, Québec, Canada;

7Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore;

8Department of Pathology, Singapore General Hospital, Singapore;

9Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P.R. China;

10Division of Bioengineering and Department of Mechanical Engineering, National University of Singapore, Singapore;12Centre for Cancer Research and Cell Biology, Queen’s University Belfast, United Kingdom;

13Mechanobiology Institute, National University of Singapore, Singapore;

14NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore;

15Liggins Institute, University of Auckland, New Zealand;

18National University Cancer Institute, Singapore;

19Renal Center, National University Hospital, Singapore;

20Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore;

21Genome Institute of Singapore, A*Star, Singapore;

22Department of Haematology-Oncology, National University Hospital, Singapore;

23Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA;

24School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia;

25Department of Biological Sciences, University of North Texas, Denton, Texas, USA.

# Corresponding authors:

Vinay Tergaonkar, Institute of Molecular and Cellular Biology, A*Star, 61 Biopolis Drive, Singapore 138673. Phone: (65) 6586-9836; Fax (65) 6779-1117; Email: vinayt[at]imcb.a-star.edu.sg

Alan Prem Kumar, Cancer Science Institute of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 14 Medical Drive, Singapore 117599. Phone: (65) 6516-5456; Fax (65) 6873-9664; Email: csiapk[at]nus.edu.sg; phcapk[at]nus.edu.sg

PubMed