Nuclear receptor coregulator SNP discovery and impact on breast cancer risk
- Equal contributors
1 Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston TX, 77030, USA
2 Lester & Sue Smith Breast Center, Baylor College of Medicine, 1 Baylor Plaza, Houston TX, 77030, USA
3 Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Voßstrasse9, 69115 Heidelberg, Germany
4 Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
5 Martin-Luther-Universitaet Halle-Wittenberg, Universitätsplatz 10, 06108 Halle, Germany
6 Division of Clinical Pharmacology, Indiana University School of Medicine, 1120 South Drive, Indianapolis, IN, 46202, USA
7 University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
8 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, Germany, 69120 Heidelberg, Germany
9 Department of Biosciences at Novum, Karolinska Institute, 14157 Huddinge, Sweden
10 Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
11 Department for Obstetrics and Gynaecology, Ludwig Maximilians Universität, Marchioninistr 15, 81377 Munich, Germany
12 Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessen, University of Heidelberg, Medical Faculty of Mannheim, Friedrich-Ebert-Str 107, 68167 Mannheim, Germany
13 Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
14 Division of Molecular Genetics, Department of Gynaecology and Obstetrics, Clinical Center University of Düsseldorf, 40225 Düsseldorf, Germany
15 Division of Oncology, Department of Gynaecology and Obstetrics, University Hospital Schleswig-Holstein, Arnold-Heller-Str 3, 24105 Kiel, Germany
16 Institut für Humangenetik, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
17 Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, Center of Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Kerpener Straße 34, 50931 Cologne, Germany
18 Division of Gynecology and Obstetrics, Klinikum rechts der Isar at the Technical University Munich, 80336 Munich, Germany
19 Departments of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston TX, 77030, USA
20 Molecular & Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston TX, 77030, USA
BMC Cancer 2009, 9:438 doi:10.1186/1471-2407-9-438Published: 14 December 2009
Coregulator proteins are "master regulators", directing transcriptional and posttranscriptional regulation of many target genes, and are critical in many normal physiological processes, but also in hormone driven diseases, such as breast cancer. Little is known on how genetic changes in these genes impact disease development and progression. Thus, we set out to identify novel single nucleotide polymorphisms (SNPs) within SRC-1 (NCoA1), SRC-3 (NCoA3, AIB1), NCoR (NCoR1), and SMRT (NCoR2), and test the most promising SNPs for associations with breast cancer risk.
The identification of novel SNPs was accomplished by sequencing the coding regions of these genes in 96 apparently normal individuals (48 Caucasian Americans, 48 African Americans). To assess their association with breast cancer risk, five SNPs were genotyped in 1218 familial BRCA1/2-mutation negative breast cancer cases and 1509 controls (rs1804645, rs6094752, rs2230782, rs2076546, rs2229840).
Through our resequencing effort, we identified 74 novel SNPs (30 in NCoR, 32 in SMRT, 10 in SRC-3, and 2 in SRC-1). Of these, 8 were found with minor allele frequency (MAF) >5% illustrating the large amount of genetic diversity yet to be discovered. The previously shown protective effect of rs2230782 in SRC-3 was strengthened (OR = 0.45 [0.21-0.98], p = 0.04). No significant associations were found with the other SNPs genotyped.
This data illustrates the importance of coregulators, especially SRC-3, in breast cancer development and suggests that more focused studies, including functional analyses, should be conducted.