title: Associations of genetic variants in the estrogen receptor coactivators PPARGC1A, PPARGC1B and EP300 with familial breast cancer.
abstract: The mitogen effect of the ovarian steroid estrogen is a strong risk factor for breast cancer development. This effect is mainly mediated by the estrogen receptor alpha, a hormone inducible transcription factor, which activates gene expression through recruiting multiple coactivators, such as PPARGC1A, PPARGC1B and EP300. We tested the hypothesis that non-conservative, putative functional amino acid exchanges in PPARGC1A, PPARGC1B and EP300 act as low-penetrance familial breast cancer risk factors. The analysis of 816 BRCA1/2 mutation-negative familial breast cancer patients and 1012 controls revealed an association of the PPARGC1A Thr612Met polymorphism with familial breast cancer (OR = 1.35, 95% CI 1.00-1.81, P = 0.049), high-risk familial breast cancer (OR = 1.51, 95% CI 1.08-2.12, P = 0.017) and bilateral familial breast cancer (OR = 2.30, 95% CI 1.24-4.28, P = 0.009). Logistic regression analyses of the PPARGC1B Ala203Pro variant showed an increased familial breast cancer risk of heterozygous and homozygous variant allele carriers (OR = 1.48, 95% CI 1.15-1.91, P = 0.002). The genotype-combination analysis of the associated PPARGC1A Thr612Met variant and the associated PPARGC1B Ala203Pro variant suggests an allele dose-dependent breast cancer risk (P(trend) = 0.0004). Our results indicate for the first time the importance of inherited variants in the estrogen receptor coactivator genes PPARGC1A and PPARGC1B for familial breast cancer susceptibility. Owing to their impact on estrogen signaling, these polymorphisms might also influence adjuvant anti-estrogen therapy, using agents such as tamoxifen and raloxifen, and outcome of breast cancer patients.
authors.affiliation: Division of Molecular Genetic Epidemiology, Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany. m.wirtenberger@dkfz.de
authors.forename: Michael
authors.initials: M
authors.lastname: Wirtenberger
authors.forename: Sandrine
authors.initials: S
authors.lastname: Tchatchou
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Julia
authors.initials: J
authors.lastname: Schmutzhard
authors.forename: Christian
authors.initials: C
authors.lastname: Sutter
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Barbara
authors.initials: B
authors.lastname: Wappenschmidt
authors.forename: Marion
authors.initials: M
authors.lastname: Kiechle
authors.forename: Norbert
authors.initials: N
authors.lastname: Arnold
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
authors.forename: Dieter
authors.initials: D
authors.lastname: Niederacher
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D050881:E1A-Associated p300 Protein / Q000235:genetics*; D005192:Family Health; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; C455622:PPARGC1B protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D014157:Transcription Factors; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human