Carcinogenesis Advance Access published online on November 20, 2008
Carcinogenesis, doi:10.1093/carcin/bgn253
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A variant affecting a putative miRNA target site in estrogen receptor one (ERS1) is associated with breast cancer risk in premenopausal women
1 Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany, Heidelberg, Germany
2 Division of Molecular Oncology, Department of Gynecology and Obstetrics, University of Heidelberg, Germany
3 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
4 Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden
5 Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
6 Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Center of Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Germany
7 Division of Gynaecology and Obstetrics, Klinikum rechts der Isar at the Technical University, Munich, Germany, 50931 Köln, Germany
8 Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessen, University of Heidelberg, Medical Faculty of Mannheim, 68167 Mannheim, Germany
9 Institute of Human Genetics, University of Regensburg, 93053, Regensburg, Germany
10 Division of Molecular Genetics, Department of Gynaecology and Obstetrics, Clinical Center University of Düsseldorf, 40225, Düsseldorf, Germany
11 Division of Oncology, Department of Gynaecology and Obstetrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
12 Institut für Humangenetik, Augustenburger Platz 1, 13353 Berlin
13 Department for Obstetrics and Gynaecology, Ludwig Maximilians Universität, Marchionini Str. 15, 81377 Munich, Germany
Corresponding author: Sandrine Tchatchou, Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany, Phone: +49-6221-421809, email: s.tchatchou{at}dkfz.de
Micro-RNAs (miRNAs) negatively regulate expression of target transcripts by hybridization to complementary sites of their mRNA targets. Chen and Rajewsky have described several putative functional SNPs in miRNA-target sites. Here, we selected 11 miRNA-target site SNPs located in 3`UTRs of genes involved in cancer and breast cancer to analyze their impact on breast cancer risk using a large familial study population. Whereas no association was observed for 10 SNPs, a significant association was revealed for the variant affecting a miRNA-target site in the estrogen receptor one (ESR1). Age stratification showed that the association was stronger in premenopausal women (C versus T: OR = 0.60, C.I. = 0.41-0.89, P = 0.010). Furthermore, the effect was stronger in high risk familial cases (C versus T: OR = 0.42, C.I. = 0.25-0.71, P = 0.0009). Clinical studies have shown that elimination of ESR1 significantly reduces breast cancer risk. Thus, therapies that inhibit ESR1 are used for breast cancer treatment. According to in-silico analysis ESR1_ rs2747648 affects the binding capacity of miR-453, which is stronger when the C- allele is present. In contrast, the T-allele attenuates the binding of miR-453, which might lead to a reduced miRNA-mediated ERS1-repression, in consequence higher ESR1 protein levels and an increased breast cancer risk. Thus, the breast cancer protective effect observed for the C-allele in premenopausal women is biological reasonable. The analysis of large study populations in multicentre collaboration will be needed to verify the association and answer questions regarding the possible impact of this variant on therapeutic and clinical outcome.
Received September 19, 2008; revised October 28, 2008; accepted November 1, 2008.