Genetic variation of ESR1 and its co-activator PPARGC1B is synergistic in augmenting the risk of estrogen receptor-positive breast cancer.
BACKGROUND
Given the role of estrogen in breast carcinogenesis and the modification of estrogen receptor (ER) activity by its biochemical cofactors, we hypothesize that genetic variation within ER cofactor genes alters cellular response to estrogen exposure and consequently modifies the risk for ER-positive breast cancer.


METHODS
We genotyped 790 tagging SNPs within 60 ER cofactor genes in 1,257 cases and 1,464 controls from Sweden and in 2,215 cases and 1,265 controls from Finland, and tested their associations with either ER-positive or ER-negative breast cancer.


RESULTS
Seven SNPs showed consistent association with ER-positive breast cancer in the two independent samples, and six of them were located within PPARGC1B, encoding an ER co-activator, with the strongest association at rs741581 (odds ratio = 1.41, P = 4.84 × 10⁻⁵) that survived Bonferroni correction for multiple testing in the combined ER-positive breast cancer sample (Pcorrected = 0.03). Moreover, we also observed significant synergistic interaction (Pinteraction = 0.008) between the genetic polymorphisms within PPARGC1B and ESR1 in ER-positive breast cancer. By contrast, no consistent association was observed in ER-negative breast cancer. Furthermore, we found that administration of estrogen in the MCF-7 cell line induced PPARGC1B expression and enhanced occupancies of ER and RNA polymerase II within the region of SNP association, suggesting the upregulation of PPARGC1B expression by ESR1 activation.


CONCLUSIONS
Our study revealed that DNA polymorphisms of PPARGC1B, coding a bona fide ER co-activator, are associated with ER-positive breast cancer risk. The feed-forward transcriptional regulatory loop between PPARGC1B and ESR1 further augments their protein interaction, which provides a plausible mechanistic explanation for the synergistic genetic interaction between PPARGC1B and ESR1 in ER-positive breast cancer. Our study also highlights that biochemically and genomically informed candidate gene studies can enhance the discovery of interactive disease susceptibility genes.
Human Genetics, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
Yuqing
Y
Li
Yi
Y
Li
Sara
S
Wedrén
Guoliang
G
Li
Tze Howe
TH
Charn
Kartiki Vasant
KV
Desai
Carine
C
Bonnard
Kamila
K
Czene
Keith
K
Humphreys
Hatef
H
Darabi
Kristjana
K
Einarsdóttir
Tuomas
T
Heikkinen
Kristiina
K
Aittomäki
Carl
C
Blomqvist
Kee Seng
KS
Chia
Heli
H
Nevanlinna
Per
P
Hall
Edison T
ET
Liu
Jianjun
J
Liu
D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins; D018570:Risk Assessment; D013548:Sweden; D014158:Transcription, Genetic
D002352:Carrier Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C455622:PPARGC1B protein, human; D016601:RNA-Binding Proteins
Am J Hum Genet. 2007 Apr;80(4):705-15
17357076
Carcinogenesis. 2005 Aug;26(8):1457-64
15845652
Methods Mol Biol. 2000;132:365-86
10547847
Mol Interv. 2005 Dec;5(6):343-57
16394250
BMC Cancer. 2009 Jan 30;9:43
19183483
Hugo J. 2009 Dec;3(1-4):31-40
21119756
Int J Cancer. 1999 Jan 18;80(2):231-6
9935204
Carcinogenesis. 2006 Nov;27(11):2201-8
16704985
BMC Cancer. 2008 Jan 14;8:6
18194538
Nature. 2009 Nov 5;462(7269):58-64
19890323
Endocr Rev. 2004 Feb;25(1):45-71
14769827
Clin Cancer Res. 2005 Mar 15;11(6):2169-74
15788663
J Natl Cancer Inst. 2009 Jul 15;101(14):1012-8
19567422
Int J Cancer. 2005 Feb 10;113(4):575-80
15472904
Clin Cancer Res. 2008 Dec 15;14(24):8000-9
19088016
Carcinogenesis. 2008 Feb;29(2):333-41
18174243
Breast Cancer Res. 2005;7(3):R353-6
15987430
J Clin Oncol. 2005 Mar 10;23(8):1616-22
15755967
Crit Rev Eukaryot Gene Expr. 2002;12(1):1-22
12433063
J Natl Cancer Inst Monogr. 2000;(27):135-45
10963625
Int J Cancer. 1999 May 5;81(3):339-44
10209946
Am J Hum Genet. 2004 Jan;74(1):106-20
14681826
Breast Cancer Res. 2004;6(4):R437-49
15217512
J Natl Cancer Inst. 2002 Apr 17;94(8):606-16
11959894
Nat Genet. 2008 Jun;40(6):703-6
18438407
PLoS Genet. 2008 Apr 25;4(4):e1000054
18437204
Nature. 2005 Oct 27;437(7063):1299-320
16255080
Cancer Epidemiol Biomarkers Prev. 2004 Oct;13(10):1558-68
15466970
Breast Cancer Res Treat. 2008 Jan;107(1):95-102
18043898
Hum Mol Genet. 2009 Mar 15;18(6):1131-9
19126777
Genome Biol. 2010;11(2):R22
20181287
Nat Genet. 2008 Jul;40(7):844-53
18511948
PLoS Genet. 2010 Jul 01;6(7):e1001012
20617168
Endocr Rev. 1999 Jun;20(3):321-44
10368774
J Biol Chem. 2007 Sep 14;282(37):26897-26907
17631495
Breast Cancer Res. 2008;10(1):R15
18271972
J Biol Chem. 2002 Apr 19;277(16):13918-25
11854298
Eur J Cancer. 2000 Jun;36(9):1143-8
10854948
Nat Genet. 2009 Mar;41(3):324-8
19219042
Nat Genet. 2007 Jul;39(7):865-9
17529974
Bioinformatics. 2005 Jan 15;21(2):263-5
15297300
Breast Cancer Res Treat. 2003 Dec;82(3):165-8
14703063
Mol Cancer. 2002 Nov 14;1:7
12473178
J Natl Cancer Inst. 2000 Sep 20;92(18):1529-31
10995809
J Natl Cancer Inst. 2004 Dec 15;96(24):1856-65
15601642
Cancer Causes Control. 1998 May;9(3):259-67
9684706
Clin Cancer Res. 2010 Apr 1;16(7):1979-87
20332324
Am J Hum Genet. 2002 Aug;71(2):432-8
12094328