Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

• Published in: American journal of human genetics Vol. 101; no. 2; pp. 255 - 266
• Main Authors: Betts, Joshua A., Moradi Marjaneh, Mahdi, Al-Ejeh, Fares, Lim, Yi Chieh, Shi, Wei, Sivakumaran, Haran, Tropée, Romain, Patch, Ann-Marie, Clark, Michael B., Bartonicek, Nenad, Wiegmans, Adrian P., Hillman, Kristine M., Kaufmann, Susanne, Bain, Amanda L., Gloss, Brian S., Crawford, Joanna, Kazakoff, Stephen, Wani, Shivangi, Wen, Shu W., Day, Bryan, Möller, Andreas, Cloonan, Nicole, Pearson, John, Brown, Melissa A., Mercer, Timothy R., Waddell, Nicola, Khanna, Kum Kum, Dray, Eloise, Dinger, Marcel E., Edwards, Stacey L., French, Juliet D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-08-2017; Elsevier
• Subjects: 11q13; breast cancer; Breast Neoplasms - genetics; Cell Line, Tumor; Chromatin - metabolism; Chromosomes, Human, Pair 11 - genetics; Cyclin D1 - genetics; DNA Breaks, Double-Stranded; DNA Damage - genetics; DNA repair; DNA Repair - genetics; enhancer; Enhancer Elements, Genetic - genetics; Estrogens - metabolism; Female; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease - genetics; GWAS; Humans; long noncoding RNAs; MCF-7 Cells; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic - genetics; RNA Interference; RNA, Guide, CRISPR-Cas Systems; RNA, Long Noncoding - genetics; RNA, Small Interfering - genetics; breast cancer; 11q13; enhancer; long noncoding RNAs; GWAS; DNA repair
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2017.07.007

Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer.