Abstract
BackgroundCoregulator 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.MethodsThe 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).ResultsThrough 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.ConclusionsThis 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.
Highlights
Coregulator proteins are "master regulators", directing transcriptional and posttranscriptional regulation of many target genes, and are critical in many normal physiological processes, and in hormone driven diseases, such as breast cancer
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
single nucleotide polymorphisms (SNPs) Discovery Target sequence obtained from NCBI consisting of all exons, 500 bp of proximal promoter, and 25 bp of flanking introns from SRC-1, SRC-3, NCoR, and SMRT was submitted for primer design and Sanger sequencing to Polymorphic DNA Technologies Inc. (Alameda CA)
Summary
SNP Discovery Target sequence obtained from NCBI consisting of all exons, 500 bp of proximal promoter, and 25 bp of flanking introns from SRC-1, SRC-3, NCoR, and SMRT was submitted for primer design and Sanger sequencing to Polymorphic DNA Technologies Inc. (Alameda CA). Genotyping for Association with Breast Cancer Risk We genotyped a case-control study of female index patients of BRCA1/BRCA2 mutation negative breast cancer families for two SNPs in SRC-3 which were previously shown to have a protective effect for breast cancer [15] (rs2230782 and rs2076546). The three SNPs that we rationalized may have functional consequences that we were able to genotype, namely SRC-1 P1272S (rs1804645), SRC-3 R218C (rs6094752), and SMRT A1706T (rs2229840), did not significantly associate with breast cancer risk (Table 2). We did not genotype the two SNPs (SMRT H52R and CALCOCO1 R12H) identified in the Haiman study to be associated with breast cancer risk since they were found either exclusively or predominantly in African Americans (European population MAF: SMRT H52R = 0%, CALCOCO1 R12H = 0.6%). Since our study exclusively contains Europeans, it was unlikely that we would obtain sufficient power to detect an association
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