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,#
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore
2 Institute of Molecular and Cellular Biology, A*Star, Singapore
3 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
4 McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Wisconsin, USA
5 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
6 Institute for research in immunology and cancer (IRIC), University of Montreal, Québec, Canada; 7 Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore
8 Department of Pathology, Singapore General Hospital, Singapore
9 Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P.R. China
10 Division of Bioengineering and Department of Mechanical Engineering, National University of Singapore, Singapore
11 Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
12 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, United Kingdom 13 Mechanobiology Institute, National University of Singapore, Singapore
14 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
15 Liggins Institute, University of Auckland, New Zealand
16 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
17 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
18 National University Cancer Institute, Singapore
19 Renal Center, National University Hospital, Singapore
20 Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore
21 Genome Institute of Singapore, A*Star, Singapore
22 Department of Haematology-Oncology, National University Hospital, Singapore
23 Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
24 School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia; 25 Department of Biological Sciences, University of North Texas, Denton, Texas, USA
Published in Journal of Clinical Investigation on 1 August 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.
Figure Legend: A model based on our studies which uncover a novel function for the RNA helicase DP103 which binds and stabilizes TAK1 and thus activates NFκB signaling. Although constitutive activation of NFκB is a well-documented phenomenon in cancer, mutations or amplicfications of enzymes such as TAK1 that could maintain IKK2 and hence NFkB in a constitutively active state are not seen in cancer cells. This study uncovers that increase in levels of DP103 marks the switch from a non-metastatic to metastatic state in breast cancer cells and possibly other cancer cell types. DP103 functions as rate limiting a co-factor of Tak1 mediated IKK2 activation. In addition, we also elucidated a plausible DP103-NFκB 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.
For more information on Vinay TERGAONKAR’s laboratory, click here.