BMC Cancer 2009, 9:438 http://www.biomedcentral.com/1471-2407/9/438 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. Background Nuclear receptors are critical for proper development and function of many physiological pathways including lipid metabolism, inflammation, and cell growth [1-3]. Over the past 25 years, it has become clear that nuclear recep- tors are also critical for the onset and progression of many diseases, including cancer. In breast cancer, for example, estrogen receptor-α (ERα) is expressed and drives tumor growth in approximately 2/3 of cases. However, only recently it has been appreciated that proper nuclear recep- tor function is absolutely dependent on the interaction with coregulator proteins [4]. These proteins couple nuclear receptors with RNA polymerase II and chromatin remodeling machinery to either activate (coactivators) or repress (corepressors) nuclear receptor mediated gene transcription. And because a single or a subset of coregu- lators can simultaneously regulate multiple cellular proc- esses through multiple nuclear receptors, they have been classified as 'master regulators' [3]. Keeping with this clas- sification, many coregulators have been implicated in numerous human diseases, including breast cancer [5- 10]. Family history is one of the strongest risk factors for breast cancer with the risk approximately double in first degree relatives of women with breast cancer compared to the general population [11]. Because of this, many attempts to identify genetic risk factors using multiple approaches have been conducted. However, despite the identification of mutations in the major risk factor genes such as BRCA1, BRCA2, PTEN, CHEK2, and ATM, it is estimated that ~75% of familial breast cancers have yet unidentified risk alleles [12]. ERα is expressed and drives a large fraction of breast cancer cases and is therefore an excellent candidate gene for identifying breast cancer risk factors. Recently, a significant association with familial breast cancer risk has been observed for the C allele of ESR1_rs2747648 in an allele dose-dependent manner. This variant is located in a miRNA-binding site in the 3' untranslated region of ESR1 [13]. However, historically very few associations have been found between SNPs in ERα and breast cancer risk. Further, a recent study conducted a comprehensive search of all SNPs in ERα that revealed no major risk associations (n>55,000 breast cancer cases and controls) [14]. This suggests that other players in the ER signaling pathway may be important for breast cancer risk. Because of the critical importance of coregulators for ERα function, we hypothesized that breast cancer risk is influenced by SNPs within the coactivators SRC-1/NCoA1 and SRC-3/ NCoA3/AIB1 and the corepressors NCoR and SMRT/ NCoR2. We previously reported two SNPs in SRC-3 (rs2230782 and rs2076546) associated with reduced breast cancer risk in a case-control study of German and Polish high-risk, BRCA1/2 mutation-negative women (cases: 775, controls: 1628) [15]. In a recent study by Haiman et al [16], coreg- ulator sequencing was conducted in 95 women with Page 2 of 9 (page number not for citation purposes)