title: Haplotypes of the estrogen receptor beta gene and breast cancer risk.
abstract: Exposure to exogenous (oral contraceptives, postmenopausal hormone therapy) and endogenous (number of ovulatory cycles, adiposity) steroid hormones is associated with breast cancer risk. Breast cancer risk associated with these exposures could hypothetically be modified by genes in the steroid hormone synthesis, metabolism and signaling pathways. Estrogen receptors are the first step along the path of signaling cell growth and development upon stimulation with estrogens. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium has systematically selected haplotype tagging SNPs in genes along the steroid hormone synthesis, metabolism and binding pathways, including the estrogen receptor beta (ESR2) gene. Four htSNPs tag the 6 major (>5% frequency) haplotypes of the ESR2 gene. These polymorphisms have been genotyped in 5,789 breast cancer cases and 7,761 controls nested within the American Cancer Society Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study and Women's Health Study cohorts. None of the SNPs were independently associated with breast cancer risk. One haplotype of the ESR2 gene was associated with breast cancer risk before correction for multiple testing (OR 1.17, 95% CI 1.07-1.28, p = 0.0007). This haplotype remained associated with breast cancer risk after adjustment for multiple testing using a permutation procedure. There was no statistically significant heterogeneity in SNP or haplotype odds ratios across cohorts. These data suggest that inherited variants in ESR2 (while possibly conferring a small increased risk of breast cancer) are not associated with appreciable (OR > 1.2) changes in breast cancer risk among Caucasian women.
authors.affiliation: Program in Molecular and Genetic Epidemiology, Epidemiology Department, Harvard School of Public Health, Boston, MA, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Cox
authors.forename: Philip
authors.initials: P
authors.lastname: Bretsky
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Paul
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authors.lastname: Pharoah
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Pilar
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authors.lastname: Amiano
authors.forename: Goran
authors.initials: G
authors.lastname: Berglund
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.forename: Julie
authors.initials: J
authors.lastname: Buring
authors.forename: Noel
authors.initials: N
authors.lastname: Burtt
authors.forename: Eugenia E
authors.initials: EE
authors.lastname: Calle
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Françoise
authors.initials: F
authors.lastname: Clavel-Chapelon
authors.forename: Graham A
authors.initials: GA
authors.lastname: Colditz
authors.forename: Heather Spencer
authors.initials: HS
authors.lastname: Feigelson
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hankinson
authors.forename: Joel
authors.initials: J
authors.lastname: Hirschhorn
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Robert
authors.initials: R
authors.lastname: Hoover
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.forename: Laurence
authors.initials: L
authors.lastname: Kolonel
authors.forename: Loic
authors.initials: L
authors.lastname: LeMarchand
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.forename: Petra H M
authors.initials: PH
authors.lastname: Peeters
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Pike
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.forename: Michael
authors.initials: M
authors.lastname: Thun
authors.forename: Anne
authors.initials: A
authors.lastname: Tjonneland
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
mesh_terms: D000328:Adult; D000483:Alleles; D001943:Breast Neoplasms / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012306:Risk; D044465:White People
chemical_list: D047629:Estrogen Receptor beta