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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.

ABSTRACT: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ?11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

SUBMITTER: Couch FJ

PROVIDER: S-EPMC4853421 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.

Couch Fergus J FJ Kuchenbaecker Karoline B KB Michailidou Kyriaki K Mendoza-Fandino Gustavo A GA Nord Silje S Lilyquist Janna J Olswold Curtis C Hallberg Emily E Agata Simona S Ahsan Habibul H Aittomäki Kristiina K Ambrosone Christine C Andrulis Irene L IL Anton-Culver Hoda H Arndt Volker V Arun Banu K BK Arver Brita B Barile Monica M Barkardottir Rosa B RB Barrowdale Daniel D Beckmann Lars L Beckmann Matthias W MW Benitez Javier J Blank Stephanie V SV Blomqvist Carl C Bogdanova Natalia V NV Bojesen Stig E SE Bolla Manjeet K MK Bonanni Bernardo B Brauch Hiltrud H Brenner Hermann H Burwinkel Barbara B Buys Saundra S SS Caldes Trinidad T Caligo Maria A MA Canzian Federico F Carpenter Jane J Chang-Claude Jenny J Chanock Stephen J SJ Chung Wendy K WK Claes Kathleen B M KB Cox Angela A Cross Simon S SS Cunningham Julie M JM Czene Kamila K Daly Mary B MB Damiola Francesca F Darabi Hatef H de la Hoya Miguel M Devilee Peter P Diez Orland O Ding Yuan C YC Dolcetti Riccardo R Domchek Susan M SM Dorfling Cecilia M CM Dos-Santos-Silva Isabel I Dumont Martine M Dunning Alison M AM Eccles Diana M DM Ehrencrona Hans H Ekici Arif B AB Eliassen Heather H Ellis Steve S Fasching Peter A PA Figueroa Jonine J Flesch-Janys Dieter D Försti Asta A Fostira Florentia F Foulkes William D WD Friebel Tara T Friedman Eitan E Frost Debra D Gabrielson Marike M Gammon Marilie D MD Ganz Patricia A PA Gapstur Susan M SM Garber Judy J Gaudet Mia M MM Gayther Simon A SA Gerdes Anne-Marie AM Ghoussaini Maya M Giles Graham G GG Glendon Gord G Godwin Andrew K AK Goldberg Mark S MS Goldgar David E DE González-Neira Anna A Greene Mark H MH Gronwald Jacek J Guénel Pascal P Gunter Marc M Haeberle Lothar L Haiman Christopher A CA Hamann Ute U Hansen Thomas V O TV Hart Steven S Healey Sue S Heikkinen Tuomas T Henderson Brian E BE Herzog Josef J Hogervorst Frans B L FB Hollestelle Antoinette A Hooning Maartje J MJ Hoover Robert N RN Hopper John L JL Humphreys Keith K Hunter David J DJ Huzarski Tomasz T Imyanitov Evgeny N EN Isaacs Claudine C Jakubowska Anna A James Paul P Janavicius Ramunas R Jensen Uffe Birk UB John Esther M EM Jones Michael M Kabisch Maria M Kar Siddhartha S Karlan Beth Y BY Khan Sofia S Khaw Kay-Tee KT Kibriya Muhammad G MG Knight Julia A JA Ko Yon-Dschun YD Konstantopoulou Irene I Kosma Veli-Matti VM Kristensen Vessela V Kwong Ava A Laitman Yael Y Lambrechts Diether D Lazaro Conxi C Lee Eunjung E Le Marchand Loic L Lester Jenny J Lindblom Annika A Lindor Noralane N Lindstrom Sara S Liu Jianjun J Long Jirong J Lubinski Jan J Mai Phuong L PL Makalic Enes E Malone Kathleen E KE Mannermaa Arto A Manoukian Siranoush S Margolin Sara S Marme Frederik F Martens John W M JW McGuffog Lesley L Meindl Alfons A Miller Austin A Milne Roger L RL Miron Penelope P Montagna Marco M Mazoyer Sylvie S Mulligan Anna M AM Muranen Taru A TA Nathanson Katherine L KL Neuhausen Susan L SL Nevanlinna Heli H Nordestgaard Børge G BG Nussbaum Robert L RL Offit Kenneth K Olah Edith E Olopade Olufunmilayo I OI Olson Janet E JE Osorio Ana A Park Sue K SK Peeters Petra H PH Peissel Bernard B Peterlongo Paolo P Peto Julian J Phelan Catherine M CM Pilarski Robert R Poppe Bruce B Pylkäs Katri K Radice Paolo P Rahman Nazneen N Rantala Johanna J Rappaport Christine C Rennert Gad G Richardson Andrea A Robson Mark M Romieu Isabelle I Rudolph Anja A Rutgers Emiel J EJ Sanchez Maria-Jose MJ Santella Regina M RM Sawyer Elinor J EJ Schmidt Daniel F DF Schmidt Marjanka K MK Schmutzler Rita K RK Schumacher Fredrick F Scott Rodney R Senter Leigha L Sharma Priyanka P Simard Jacques J Singer Christian F CF Sinilnikova Olga M OM Soucy Penny P Southey Melissa M Steinemann Doris D Stenmark-Askmalm Marie M Stoppa-Lyonnet Dominique D Swerdlow Anthony A Szabo Csilla I CI Tamimi Rulla R Tapper William W Teixeira Manuel R MR Teo Soo-Hwang SH Terry Mary B MB Thomassen Mads M Thompson Deborah D Tihomirova Laima L Toland Amanda E AE Tollenaar Robert A E M RA Tomlinson Ian I Truong Thérèse T Tsimiklis Helen H Teulé Alex A Tumino Rosario R Tung Nadine N Turnbull Clare C Ursin Giski G van Deurzen Carolien H M CH van Rensburg Elizabeth J EJ Varon-Mateeva Raymonda R Wang Zhaoming Z Wang-Gohrke Shan S Weiderpass Elisabete E Weitzel Jeffrey N JN Whittemore Alice A Wildiers Hans H Winqvist Robert R Yang Xiaohong R XR Yannoukakos Drakoulis D Yao Song S Zamora M Pilar MP Zheng Wei W Hall Per P Kraft Peter P Vachon Celine C Slager Susan S Chenevix-Trench Georgia G Pharoah Paul D P PD Monteiro Alvaro A N AA García-Closas Montserrat M Easton Douglas F DF Antoniou Antonis C AC

Nature communications 20160427

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 ...[more]

PMID: 27117709

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Project description:IntroductionOestrogens can mediate some of their cell survival properties through a nongenomic mechanism that involves the mitogen-activated protein kinase (MAPK) pathway. The mechanism of this rapid signalling and its dependence on a membrane bound oestrogen receptor (ER), however, remains controversial. The role of G-protein-coupled receptor and epidermal growth factor (EGF) receptor in an ER-independent signalling pathway modulated by oestrogen was investigated.MethodsER-positive and ER-negative breast cancer cell lines (MCF-7 and SKBR3) and primary breast cancer cell cultures were used in this study. Cell proliferation was assessed using standard MTT assays. Protein and cAMP levels were detected by Western blotting and ELISA, respectively. Antigen localization was performed by immunocytochemistry, immunohistochemistry and immunofluorescence. Protein knockdown was achieved using small interfering RNA technologies.ResultsEGF and oestrogen, alone and in combination, induced cell proliferation and phosphorylation of MAPK proteins Raf and ERK (extracellular signal regulated kinase)1/2 in both ER-negative SKBR3 and ER-positive MCF-7 human breast cancer cell lines. Increased Raf phosphorylation was also observed in primary human breast cultures derived from ER-positive and ER-negative breast tumours. Oestrogen induced an increase in intracellular cAMP in ER-negative SKBR3 human breast cancer cells. Oestrogen-mediated cell growth and phosphorylation of MAPK was modified by the EGF receptor antagonist AG1478, the G-protein antagonist pertussis toxin, and the angiotensin II receptor antagonist saralasin. Knockdown of angiotensin II type 1 receptor (AT1) protein expression with small interfering RNA attenuated oestrogen-induced Raf phosphorylation in ER-negative cells. AT1 receptor was found to be expressed in the cell membrane of breast tumour epithelial cells.ConclusionThese findings provide evidence that, in breast cancer cells, oestrogen can signal through AT1 to activate early cell survival mechanisms in an ER-independent manner.

Project description:IntroductionAn emerging hypothesis suggests that cytokines could play an important role in cancer as potential modulators of angiogenesis and leucocyte infiltration.MethodsA novel multiplexed flow cytometry technology was used to measure the expression of 17 cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 [p70], IL-13, IL-17, granulocyte colony-stimulating factor [CSF], granulocyte-macrophage CSF, IFN-gamma, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1beta, tumour necrosis factor [TNF]-alpha) at the protein level in 105 breast carcinoma. B lymphocyte, T lymphocyte and macrophage levels were determined by immunohistochemistry.ResultsFourteen of the 17 cytokines were expressed in breast carcinoma, whereas only nine cytokines could be detected in normal breast. Most cytokines were more abundant in breast carcinoma than in normal breast, with IL-6, IL-8, granulocyte CSF, IFN-gamma, MCP-1 and MIP-1beta being very abundant. IL-2, IL-6, IL-8, IL-10, IFN-gamma, MCP-1, MIP-1beta and TNF-alpha, and to a lesser extent IL-1beta and IL-13 exhibited levels of expression that were inversely correlated to oestrogen receptor and progesterone receptor status. Most cytokines were not correlated with age at cancer diagnosis, tumour size, histological type, or lymph node status. However, IL-1beta, IL-6, IL-8, IL-10, IL-12, MCP-1 and MIP-1beta were more abundant in high-grade tumours than in low-grade tumours. In addition, IL-8 and MIP-1beta were expressed to a greater degree in HER2-positive than in HER2-negative patients. The expression of most of the studied cytokines was correlated to levels of activator protein-1, which is known to regulate numerous cytokines. Overexpression of MCP-1 and MIP-1beta were linked to B lymphocyte, T lymphocyte and macrophage infiltration, whereas high levels of IL-8 were correlated with high macrophage content in tumour. Moreover, IL-8 positive tumours exhibited increased vascularization.ConclusionWe found that multiple cytokines were overexpressed in oestrogen receptor negative breast carcinoma, and that the three major cytokines--MCP-1, MIP-1beta and IL-8--were correlated with inflammatory cell component, which could account for the aggressiveness of these tumours.

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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.

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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.

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