Open Access Research article

Nuclear receptor coregulator SNP discovery and impact on breast cancer risk

Ryan J Hartmaier12, Sandrine Tchatchou34, Alexandra S Richter25, Jay Wang2, Sean E McGuire20, Todd C Skaar6, Jimmy M Rae7, Kari Hemminki89, Christian Sutter10, Nina Ditsch11, Peter Bugert12, Bernhard HF Weber13, Dieter Niederacher14, Norbert Arnold15, Raymonda Varon-Mateeva16, Barbara Wappenschmidt17, Rita K Schmutzler17, Alfons Meindl18, Claus R Bartram10, Barbara Burwinkel34 and Steffi Oesterreich119220*

  • * Corresponding author: Steffi Oesterreich steffio@bcm.edu

  • † Equal contributors

Author Affiliations

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

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BMC Cancer 2009, 9:438  doi:10.1186/1471-2407-9-438

Published: 14 December 2009

Abstract

Background

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.

Methods

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).

Results

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.

Conclusions

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.