Principles Governing A-to-I RNA Editing in the Breast Cancer Transcriptome

• A-to-I editing is a major source of mRNA variability in breast and other cancers
• RNA editing is globally controlled by tumor interferon and ADAR copy number
• Both these factors are highly prevalent among human cancers
• RNA editing sites might represent a new class of therapeutic targets

SummaryLittle is known about how RNA editing operates in cancer. Transcriptome analysis of 68 normal and cancerous breast tissues revealed that the editing enzyme ADAR acts uniformly, on the same loci, across tissues. In controlled ADAR expression experiments, the editing frequency increased at all loci with ADAR expression levels according to the logistic model. Loci-specific “editabilities,” i.e., propensities to be edited by ADAR, were quantifiable by fitting the logistic function to dose-response data. The editing frequency was increased in tumor cells in comparison to normal controls. Type I interferon response and ADAR DNA copy number together explained 53% of ADAR expression variance in breast cancers. ADAR silencing using small hairpin RNA lentivirus transduction in breast cancer cell lines led to less cell proliferation and more apoptosis. A-to-I editing is a pervasive, yet reproducible, source of variation that is globally controlled by 1q amplification and inflammation, both of which are highly prevalent among human cancers.

Graphical AbstractFigure optionsDownload as PowerPoint slide