Carcinogenesis Advance Access originally published online on November 20, 2008
Carcinogenesis 2009 30(1):59-64; doi:10.1093/carcin/bgn253
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A variant affecting a putative miRNA target site in estrogen receptor (ESR) 1 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
2 Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, 69115 Heidelberg, Germany
3 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
4 Department of Biosciences at Novum, Karolinska Institute, 14157 Huddinge, Sweden
5 Institute of Human Genetics, University of Heidelberg, 69120 Heidelberg, Germany
6 Department of Gynaecology and Obstetrics, Division of Molecular Gynaeco-Oncology, Center of Molecular Medicine Cologne, University Hospital of Cologne, 50931 Cologne, Germany
7 Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessen, University of Heidelberg, Medical Faculty of Mannheim, 68167 Mannheim, Germany
8 Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany
9 Department of Gynaecology and Obstetrics, Division of Molecular Genetics, Clinical Center University of Düsseldorf, 40225 Düsseldorf, Germany
10 Department of Gynecology and Obstetrics, Division of Oncology, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
11 Institut für Humangenetik, Augustenburger Platz 1, 13353 Berlin, Germany
12 Department for Obstetrics and Gynaecology, Ludwig Maximilians Universität, Marchionini Street 15, 81377 Munich, Germany
13 Division of Gynaecology and Obstetrics, Klinikum rechts der Isar at the Technical University, 80336 Munich, Germany
* To whom correspondence should be addressed. Tel: +49 6221 421809; Fax: +49 6221 421810; Email: s.tchatchou{at}dkfz.de
MicroRNAs (miRNAs) negatively regulate expression of target transcripts by hybridization to complementary sites of their messenger RNA targets. Chen et al. have described several putative functional single nucleotide polymorphisms (SNPs) in miRNA target sites. Here, we selected 11 miRNA target site SNPs located in 3' untranslated regions 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 (ESR) 1. Age stratification showed that the association was stronger in premenopausal women [C versus T: odds ratio (OR) = 0.60, confidence interval (CI) = 0.41–0.89, P = 0.010]. Furthermore, the effect was stronger in high-risk familial cases (C versus T: OR = 0.42, CI = 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 ESR1 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 biologically 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.
Abbreviations: CI, confidence interval; ESR, estrogen receptor; miRNA, microRNA; OR, odds ratio; SNP, single nucleotide polymorphism
Received September 19, 2008; revised October 28, 2008; accepted November 1, 2008.