MiR-1287-5p has inhibitory effects on breast cancer growth mediated by interaction with phosphoinositide 3-kinase CB (miR-1287-5p overexpression study)

Background: Non-coding RNAs and especially microRNAs have been discovered as master regulators of cancer initiation and progression. The aim of our study was to discover and characterize the function of yet uncharacterized microRNAs in human breast carcinogenesis. Methods: In an unbiased approach, we made use of a commonly used model system for breast cancer (BC) stem cells (mammospheres) to identify whole miRNome alterations with a special focus on previously uncharacterized miRNAs in BC. We further characterized the influence of microRNA-1287-5p, a yet uncharacterized microRNA in BC, in patient samples (n=1262) and on several hallmarks of cancer in vitro and in vivo with a special focus on triple negative BC. The molecular mode of action was further characterized using whole transcriptome analysis, in silico prediction tools, miRNA-interaction luciferase assays and pheno-copy assays. Results: We identified miR-1287-5p among many others as differentially expressed in mammospheres. Clinical validation indicated that miR-1287-5p is significantly downregulated in human BC and associated with poor prognosis. This clinical finding can be explained by miR-1287-5p mediated growth inhibitory effects, G1 cell cycle arrest, decreased anchorage-independent growth and tumor growth in vivo. Finally, we identified PIK3CB as a direct molecular interactor of miR-1287-5p and a pheno-copy factor for miR-1287-5p. Finally, targeting PI3K-signaling pathway with chemical inhibitors together with miR-1287-5p mimics increased the pharmacological growth inhibitory potential. Conclusion: In conclusion, our data identified for the first time an involvement of miR-1287-5p in human BC and suggest a potential for therapeutic interventions in hardly to treat triple negative BC.

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