PT  - JOURNAL ARTICLE
AU  - Debora Fumagalli
AU  - David Gacquer
AU  - Françoise Rothé
AU  - Anne Lefort
AU  - Frederick Libert
AU  - David Brown
AU  - Naima Kheddoumi
AU  - Adam Shlien
AU  - Tomasz Konopka
AU  - Roberto Salgado
AU  - Denis Larsimont
AU  - Kornelia Polyak
AU  - Karen Willard-Gallo
AU  - Christine Desmedt
AU  - Martine Piccart
AU  - Marc Abramowicz
AU  - Peter J Campbell
AU  - Christos Sotiriou
AU  - Vincent Detours
TI  - Principles governing A-to-I RNA editing in the breast cancer transcriptome
AID  - 10.1101/012849
DP  - 2015 Jan 01
TA  - bioRxiv
PG  - 012849
4099  - http://biorxiv.org/content/early/2015/01/16/012849.short
4100  - http://biorxiv.org/content/early/2015/01/16/012849.full
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.