MiR-449a promotes breast cancer progression by targeting CRIP2
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Wei Shi1, Jeff Bruce1, Matthew Lee1, Shijun Yue1, Matthew Rowe1, Melania Pintilie2, Ryunosuke Kogo1, Pierre-Antoine Bissey1, Anthony Fyles3,4, Kenneth W. Yip1, Fei-Fei Liu1,3,4,5
1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
2Division of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
3Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Canada
4Department of Radiation Oncology, University of Toronto, Toronto, Canada
5Department of Medical Biophysics, University of Toronto, Toronto, Canada
Fei-Fei Liu, e-mail: Fei-Fei.Liu@rmp.uhn.on.ca
Keywords: breast cancer, miR-449a, metastasis, CRIP2, prognostic marker
Received: December 18, 2015 Accepted: February 14, 2016 Published: February 26, 2016
The identification of prognostic biomarkers and their underlying mechanisms of action remain of great interest in breast cancer biology. Using global miRNA profiling of 71 lymph node-negative invasive ductal breast cancers and 5 normal mammary epithelial tissues, we identified miR-449a to be highly overexpressed in the malignant breast tissue. Its expression was significantly associated with increased incidence of patient relapse, decreased overall survival, and decreased disease-free survival. In vitro, miR-449a promoted breast cancer cell proliferation, clonogenic survival, migration, and invasion. By utilizing a tri-modal in silico approach for target identification, Cysteine-Rich Protein 2 (CRIP2; a transcription factor) was identified as a direct target of miR-449a, corroborated using qRT-PCR, Western blot, and luciferase reporter assays. MDA-MB-231 cells stably transfected with CRIP2 demonstrated a significant reduction in cell viability, migration, and invasion, as well as decreased tumor growth and angiogenesis in mouse xenograft models. Our data revealed that overexpression of miR-449a suppresses CRIP2, which then affects the tumor vasculature, likely via NF-κB/p65 complex-mediated transcription of VEGF. These finding define an oncogenic function of miR-449a in human breast cancer, and highlight the importance of this pathway in driving aggressive behaviour.
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