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

ABSTRACT: 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.

SUBMITTER: French JD

PROVIDER: S-EPMC3617380 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

French Juliet D JD Ghoussaini Maya M Edwards Stacey L SL Meyer Kerstin B KB Michailidou Kyriaki K Ahmed Shahana S Khan Sofia S Maranian Mel J MJ O'Reilly Martin M Hillman Kristine M KM Betts Joshua A JA Carroll Thomas T Bailey Peter J PJ Dicks Ed E Beesley Jonathan J Tyrer Jonathan J Maia Ana-Teresa AT Beck Andrew A Knoblauch Nicholas W NW Chen Constance C Kraft Peter P Barnes Daniel D González-Neira Anna A Alonso M Rosario MR Herrero Daniel D Tessier Daniel C DC Vincent Daniel D Bacot Francois F Luccarini Craig C Baynes Caroline C Conroy Don D Dennis Joe J Bolla Manjeet K MK Wang Qin Q Hopper John L JL Southey Melissa C MC Schmidt Marjanka K MK Broeks Annegien A Verhoef Senno S Cornelissen Sten S Muir Kenneth K Lophatananon Artitaya A Stewart-Brown Sarah S Siriwanarangsan Pornthep P Fasching Peter A PA Loehberg Christian R CR Ekici Arif B AB Beckmann Matthias W MW Peto Julian J dos Santos Silva Isabel I Johnson Nichola N Aitken Zoe Z Sawyer Elinor J EJ Tomlinson Ian I Kerin Michael J MJ Miller Nicola N Marme Frederik F Schneeweiss Andreas A Sohn Christof C Burwinkel Barbara B Guénel Pascal P Truong Thérèse T Laurent-Puig Pierre P Menegaux Florence F Bojesen Stig E SE Nordestgaard Børge G BG Nielsen Sune F SF Flyger Henrik H Milne Roger L RL Zamora M Pilar MP Arias Perez Jose Ignacio JI Benitez Javier J Anton-Culver Hoda H Brenner Hermann H Müller Heiko H Arndt Volker V Stegmaier Christa C Meindl Alfons A Lichtner Peter P Schmutzler Rita K RK Engel Christoph C Brauch Hiltrud H Hamann Ute U Justenhoven Christina C Aaltonen Kirsimari K Heikkilä Päivi P Aittomäki Kristiina K Blomqvist Carl C Matsuo Keitaro K Ito Hidemi H Iwata Hiroji H Sueta Aiko A Bogdanova Natalia V NV Antonenkova Natalia N NN Dörk Thilo T Lindblom Annika A Margolin Sara S Mannermaa Arto A Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana M JM Wu Anna H AH Tseng Chiu-chen CC Van Den Berg David D Stram Daniel O DO Lambrechts Diether D Peeters Stephanie S Smeets Ann A Floris Giuseppe G Chang-Claude Jenny J Rudolph Anja A Nickels Stefan S Flesch-Janys Dieter D Radice Paolo P Peterlongo Paolo P Bonanni Bernardo B Sardella Domenico D Couch Fergus J FJ Wang Xianshu X Pankratz Vernon S VS Lee Adam A Giles Graham G GG Severi Gianluca G Baglietto Laura L Haiman Christopher A CA Henderson Brian E BE Schumacher Fredrick F Le Marchand Loic L Simard Jacques J Goldberg Mark S MS Labrèche France F Dumont Martine M Teo Soo Hwang SH Yip Cheng Har CH Ng Char-Hong CH Vithana Eranga Nishanthie EN Kristensen Vessela V Zheng Wei W Deming-Halverson Sandra S Shrubsole Martha M Long Jirong J Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Grip Mervi M Andrulis Irene L IL Knight Julia A JA Glendon Gord G Mulligan Anna Marie AM Devilee Peter P Seynaeve Caroline C García-Closas Montserrat M Figueroa Jonine J Chanock Stephen J SJ Lissowska Jolanta J Czene Kamila K Klevebring Daniel D Schoof Nils N Hooning Maartje J MJ Martens John W M JW Collée J Margriet JM Tilanus-Linthorst Madeleine M Hall Per P Li Jingmei J Liu Jianjun J Humphreys Keith K Shu Xiao-Ou XO Lu Wei W Gao Yu-Tang YT Cai Hui H Cox Angela A Balasubramanian Sabapathy P SP Blot William W Signorello Lisa B LB Cai Qiuyin Q Pharoah Paul D P PD Healey Catherine S CS Shah Mitul M Pooley Karen A KA Kang Daehee D Yoo Keun-Young KY Noh Dong-Young DY Hartman Mikael M Miao Hui H Sng Jen-Hwei JH Sim Xueling X Jakubowska Anna A Lubinski Jan J Jaworska-Bieniek Katarzyna K Durda Katarzyna K Sangrajrang Suleeporn S Gaborieau Valerie V McKay James J Toland Amanda E AE Ambrosone Christine B CB Yannoukakos Drakoulis D Godwin Andrew K AK Shen Chen-Yang CY Hsiung Chia-Ni CN Wu Pei-Ei PE Chen Shou-Tung ST Swerdlow Anthony A Ashworth Alan A Orr Nick N Schoemaker Minouk J MJ Ponder Bruce A J BA Nevanlinna Heli H Brown Melissa A MA Chenevix-Trench Georgia G Easton Douglas F DF Dunning Alison M AM

American journal of human genetics 20130327 4

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 i ...[more]

PMID: 23540573

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Project description:BACKGROUND: Cyclin D1 is a well-characterised cell cycle regulator with established oncogenic capabilities. Despite these properties, studies report contrasting links to tumour aggressiveness. It has previously been shown that silencing cyclin D1 increases the migratory capacity of MDA-MB-231 breast cancer cells with concomitant increase in 'inhibitor of differentiation 1' (ID1) gene expression. Id1 is known to be associated with more invasive features of cancer and with the epithelial-mesenchymal transition (EMT). Here, we sought to determine if the increase in cell motility following cyclin D1 silencing was mediated by Id1 and enhanced EMT-features. To further substantiate these findings we aimed to delineate the link between CCND1, ID1 and EMT, as well as clinical properties in primary breast cancer. METHODS: Protein and gene expression of ID1, CCND1 and EMT markers were determined in MDA-MB-231 and ZR75 cells by western blot and qPCR. Cell migration and promoter occupancy were monitored by transwell and ChIP assays, respectively. Gene expression was analysed from publicly available datasets. RESULTS: The increase in cell migration following cyclin D1 silencing in MDA-MB-231 cells was abolished by Id1 siRNA treatment and we observed cyclin D1 occupancy of the Id1 promoter region. Moreover, ID1 and SNAI2 gene expression was increased following cyclin D1 knock-down, an effect reversed with Id1 siRNA treatment. Similar migratory and SNAI2 increases were noted for the ER-positive ZR75-1 cell line, but in an Id1-independent manner. In a meta-analysis of 1107 breast cancer samples, CCND1low/ID1high tumours displayed increased expression of EMT markers and were associated with reduced recurrence free survival. Finally, a greater percentage of CCND1low/ID1high tumours were found in the EMT-like 'claudin-low' subtype of breast cancer than in other subtypes. CONCLUSIONS: These results indicate that increased migration of MDA-MB-231 cells following cyclin D1 silencing can be mediated by Id1 and is linked to an increase in EMT markers. Moreover, we have confirmed a relationship between cyclin D1, Id1 and EMT in primary breast cancer, supporting our in vitro findings that low cyclin D1 expression can be linked to aggressive features in subgroups of breast cancer.

Dataset Information

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

Publications

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

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