Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

• Published in: American journal of human genetics Vol. 92; no. 4; pp. 489 - 503
• Main Authors: Ghoussaini, Maya, Edwards, Stacey L., Meyer, Kerstin B., Ahmed, Shahana, Betts, Joshua A., Dicks, Ed, Beesley, Jonathan, Tyrer, Jonathan, Barnes, Daniel, Alonso, M. Rosario, Tessier, Daniel C., Luccarini, Craig, Baynes, Caroline, Bolla, Manjeet K., Wang, Qin, Southey, Melissa C., Schmidt, Marjanka K., Broeks, Annegien, Verhoef, Senno, Cornelissen, Sten, Muir, Kenneth, Lophatananon, Artitaya, Siriwanarangsan, Pornthep, Loehberg, Christian R., Ekici, Arif B., dos Santos Silva, Isabel, Johnson, Nichola, Tomlinson, Ian, Truong, Thérèse, Menegaux, Florence, Bojesen, Stig E., Nordestgaard, Børge G., Nielsen, Sune F., Flyger, Henrik, Milne, Roger L., Benitez, Javier, Anton-Culver, Hoda, Brenner, Hermann, Stegmaier, Christa, Meindl, Alfons, Aittomäki, Kristiina, Matsuo, Keitaro, Iwata, Hiroji, Antonenkova, Natalia N., Dörk, Thilo, Mannermaa, Arto, Stram, Daniel O., Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo, Bonanni, Bernardo, Couch, Fergus J., Pankratz, Vernon S., Giles, Graham G., Severi, Gianluca, Haiman, Christopher A., Schumacher, Fredrick, Simard, Jacques, Goldberg, Mark S., Dumont, Martine, Teo, Soo Hwang, Yip, Cheng Har, Vithana, Eranga Nishanthie, Kristensen, Vessela, Zheng, Wei, Pylkäs, Katri, Glendon, Gord, Seynaeve, Caroline, Figueroa, Jonine, Lissowska, Jolanta, Schoof, Nils, Martens, John W.M., Collée, J. Margriet, Tilanus-Linthorst, Madeleine, Hall, Per, Humphreys, Keith, Shu, Xiao-Ou, Gao, Yu-Tang, Cai, Hui, Cox, Angela, Balasubramanian, Sabapathy P., Blot, William, Pharoah, Paul D.P., Healey, Catherine S., Pooley, Karen A., Yoo, Keun-Young, Miao, Hui, Sim, Xueling, Jaworska-Bieniek, Katarzyna, Gaborieau, Valerie, Toland, Amanda E., Chen, Shou-Tung, Swerdlow, Anthony, Ashworth, Alan, Schoemaker, Minouk J., Nevanlinna, Heli, Chenevix-Trench, Georgia, Easton, Douglas F., Dunning, Alison M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.04.2013; Cell Press; Elsevier
• Subjects: Binding Sites; Breast cancer; Breast Neoplasms - genetics; Case-Control Studies; Cell Line, Tumor; Chromatin; Chromatin - chemistry; Chromatin - genetics; Chromatin Immunoprecipitation; Chromosomes, Human, Pair 11 - genetics; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclin-dependent kinases; Electrophoretic Mobility Shift Assay; Enhancer Elements, Genetic - genetics; ets-Domain Protein Elk-4 - antagonists & inhibitors; ets-Domain Protein Elk-4 - genetics; ets-Domain Protein Elk-4 - metabolism; Female; GATA3 Transcription Factor - antagonists & inhibitors; GATA3 Transcription Factor - genetics; GATA3 Transcription Factor - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Luciferases - metabolism; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic - genetics; Proteins; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Signal transduction; Silencer Elements, Transcriptional - genetics; Europe
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2013.01.002

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.