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 DayAndreas 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

Research output: Contribution to journalArticle

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)255-266
Number of pages12
JournalAmerican Journal of Human Genetics
Volume101
Issue number2
DOIs
StatePublished - Aug 3 2017
Externally publishedYes

Keywords

  • 11q13
  • DNA repair
  • GWAS
  • breast cancer
  • enhancer
  • long noncoding RNAs

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Betts, J. A., Moradi Marjaneh, M., Al-Ejeh, F., Lim, Y. C., Shi, W., Sivakumaran, H., Tropée, R., Patch, A. M., Clark, M. B., Bartonicek, N., Wiegmans, A. P., Hillman, K. M., Kaufmann, S., Bain, A. L., Gloss, B. S., Crawford, J., Kazakoff, S., Wani, S., Wen, S. W., ... French, J. D. (2017). Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage. American Journal of Human Genetics, 101(2), 255-266. https://doi.org/10.1016/j.ajhg.2017.07.007