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

Joshua A Betts; Mahdi Moradi Marjaneh; Fares Al-Ejeh; Yi Chieh Lim; Wei Shi; Haran Sivakumaran; Romain Tropée; Ann-Marie Patch; Michael B Clark; Nenad Bartonicek; Adrian P Wiegmans; Kristine M Hillman; Susanne Kaufmann; Amanda L Bain; Brian S Gloss; Joanna Crawford; Stephen Kazakoff; Shivangi Wani; Shu W Wen; Bryan Day; Andreas Möller; Nicole Cloonan; John Pearson; Melissa A Brown; Timothy R Mercer; Nicola Waddell; Kum Kum Khanna; Eloise Dray; Marcel E Dinger; Stacey L Edwards; Juliet D French

doi:10.1016/j.ajhg.2017.07.007

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

Am J Hum Genet. 2017 Aug 3;101(2):255-266. doi: 10.1016/j.ajhg.2017.07.007.

Authors

Joshua A Betts¹, Mahdi Moradi Marjaneh², Fares Al-Ejeh², Yi Chieh Lim², Wei Shi², Haran Sivakumaran², Romain Tropée³, Ann-Marie Patch², Michael B Clark⁴, Nenad Bartonicek⁵, Adrian P Wiegmans², Kristine M Hillman², Susanne Kaufmann², Amanda L Bain², Brian S Gloss⁵, Joanna Crawford⁶, Stephen Kazakoff², Shivangi Wani², Shu W Wen², Bryan Day², Andreas Möller², Nicole Cloonan², John Pearson², Melissa A Brown⁷, Timothy R Mercer⁵, Nicola Waddell², Kum Kum Khanna², Eloise Dray⁸, Marcel E Dinger⁵, Stacey L Edwards⁹, Juliet D French¹⁰

Affiliations

¹ Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia.
² Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
³ Queensland University of Technology at the Translational Research Institute, Brisbane, QLD 4102, Australia.
⁴ Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX1 2JD, UK; Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁵ Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
⁷ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia.
⁸ Queensland University of Technology at the Translational Research Institute, Brisbane, QLD 4102, Australia; Queensland University of Technology, Institute of Health and Biomedical Innovation, Brisbane, QLD 4059, Australia.
⁹ Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. Electronic address: stacey.edwards@qimrberghofer.edu.au.
¹⁰ Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. Electronic address: juliet.french@qimrberghofer.edu.au.

Abstract

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.

Keywords: 11q13; DNA repair; GWAS; breast cancer; enhancer; long noncoding RNAs.

MeSH terms

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 / genetics*
Enhancer Elements, Genetic / genetics
Estrogens / metabolism
Female
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease / genetics
Humans
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

Substances

CCND1 protein, human
Chromatin
Estrogens
RNA, Long Noncoding
RNA, Small Interfering
Cyclin D1