title: MiR-449a promotes breast cancer progression by targeting CRIP2.
abstract: 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.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Jeff
authors.initials: J
authors.lastname: Bruce
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lee
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Shijun
authors.initials: S
authors.lastname: Yue
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Rowe
authors.affiliation: Division of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Kogo
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Bissey
authors.affiliation: Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Fyles
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Yip
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000502:physiology; D018450:Disease Progression; D005260:Female; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D011379:Prognosis; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C486176:CRIP2 protein, human; D060588:LIM Domain Proteins; C544530:MIRN449 microRNA, human; D035683:MicroRNAs
keywords: CRIP2; breast cancer; metastasis; miR-449a; prognostic marker