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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 9 Pg. 3807-24 (Sep 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 25083991 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• I-kappa B Kinase
• IKBKB protein, human
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7
• MMP9 protein, human
• Matrix Metalloproteinase 9
• DDX20 protein, human
• DEAD Box Protein 20

Topics

• Breast Neoplasms (mortality, pathology)
• Cell Line, Tumor
• Cell Movement
• DEAD Box Protein 20 (analysis, genetics, physiology)
• Female
• Humans
• I-kappa B Kinase (metabolism)
• MAP Kinase Kinase Kinases (physiology)
• Matrix Metalloproteinase 9 (analysis, genetics)
• NF-kappa B (physiology)
• Neoplasm Invasiveness
• Neoplasm Metastasis