RT Journal Article SR Electronic T1 Principles governing A-to-I RNA editing in the breast cancer transcriptome JF bioRxiv FD Cold Spring Harbor Laboratory SP 012849 DO 10.1101/012849 A1 Debora Fumagalli A1 David Gacquer A1 Françoise Rothé A1 Anne Lefort A1 Frederick Libert A1 David Brown A1 Naima Kheddoumi A1 Adam Shlien A1 Tomasz Konopka A1 Roberto Salgado A1 Denis Larsimont A1 Kornelia Polyak A1 Karen Willard-Gallo A1 Christine Desmedt A1 Martine Piccart A1 Marc Abramowicz A1 Peter J Campbell A1 Christos Sotiriou A1 Vincent Detours YR 2015 UL http://biorxiv.org/content/early/2015/01/16/012849.abstract AB A-to-I editing substitutes inosines for adenosines at specific positions in mRNAs and can substantially alter a cell’s transcriptome. Currently, little 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. Controlled ADAR expression experiments demonstrated that the editing frequency at all loci is proportional to both ADAR expression levels and the individual locus’ editability—a propensity to be edited determined by the surrounding nucleotide sequence. Comparison of tumor transcriptomes to those of normal breast and breast organoids, i.e. pure normal breast epithelial cells, demonstrated that the editing frequency is increased in tumor cells. This was consistent with ADAR immunohistochemistry. We also demonstrated that type I interferon response and ADAR DNA copy number explain together 53% of ADAR expression in breast cancers, an observation also valid in nearly all of 20 other cancer types in The Cancer Genome Atlas. Interferon exposure increased ADAR mRNA, protein expression and editing in four breast cell lines. Finally, ADAR silencing using shRNA lentivirus transduction in breast cancer cell lines led to more cell proliferation and less apoptosis. Our results reveal that A-to-I editing is a pervasive, yet reproducible, source of variation that is controlled by two factors, 1q amplification and inflammation, both highly prevalent among human cancers. This suggests the potential for a new class of therapeutic targets and an unexpected role for inflammation in cancers.