Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers

Juliet D French, Maya Ghoussaini, Stacey L Edwards, Kerstin B Meyer, Kyriaki Michailidou, Shahana Ahmed, Sofia Khan, Mel J Maranian, Martin O'Reilly, Kristine M Hillman, Joshua A Betts, Thomas Carroll, Peter J Bailey, Ed Dicks, Jonathan Beesley, Jonathan Tyrer, Ana-Teresa Maia, Andrew Beck, Nicholas W Knoblauch, Constance ChenPeter Kraft, Daniel Barnes, Anna González-Neira, M Rosario Alonso, Daniel Herrero, Daniel C Tessier, Daniel Vincent, Francois Bacot, Craig Luccarini, Caroline Baynes, Don Conroy, Joe Dennis, Manjeet K Bolla, Qin Wang, John L Hopper, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Senno Verhoef, Sten Cornelissen, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A Fasching, Christian R Loehberg, Arif B Ekici, Matthias W Beckmann, Julian Peto, Jonine Figueroa, GENICA Network, Ian Tomlinson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

Original languageEnglish
Pages (from-to)489-503
Number of pages15
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 4 Apr 2013

Keywords / Materials (for Non-textual outputs)

  • Binding Sites
  • Breast Neoplasms
  • Case-Control Studies
  • Cell Line, Tumor
  • Chromatin
  • Chromatin Immunoprecipitation
  • Chromosomes, Human, Pair 11
  • Cyclin D1
  • Electrophoretic Mobility Shift Assay
  • Enhancer Elements, Genetic
  • Female
  • GATA3 Transcription Factor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Luciferases
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • RNA, Messenger
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Silencer Elements, Transcriptional
  • ets-Domain Protein Elk-4


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