Nuclear receptor coregulator SNP discovery and impact on breast cancer risk.
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.
Hartmaier
Ryan J
RJ
Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA. hartmaie@bcm.edu
Tchatchou
Sandrine
S
Richter
Alexandra S
AS
Wang
Jay
J
McGuire
Sean E
SE
Skaar
Todd C
TC
Rae
Jimmy M
JM
Hemminki
Kari
K
Sutter
Christian
C
Ditsch
Nina
N
Bugert
Peter
P
Weber
Bernhard H F
BH
Niederacher
Dieter
D
Arnold
Norbert
N
Varon-Mateeva
Raymonda
R
Wappenschmidt
Barbara
B
Schmutzler
Rita K
RK
Meindl
Alfons
A
Bartram
Claus R
CR
Burwinkel
Barbara
B
Oesterreich
Steffi
S
D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D056918:Nuclear Receptor Coactivators / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics; D055815:Young Adult
D056918:Nuclear Receptor Coactivators