title: Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects.
abstract: OBJECTIVE
  To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case-control study in North Carolina.
  
  
  METHODS
  Cases (n = 1,972) were women 20-74 years old and diagnosed with breast cancer between 1993 and 2001. Population-based controls (n = 1,776) were frequency matched to cases by age and race. A total of 195 SNPs were genotyped, and linkage disequilibrium was evaluated using the r (2) statistic. Odds ratios (ORs) and 95 % confidence intervals (CIs) for associations with breast cancer overall and by molecular subtype were estimated using logistic regression. Monte Carlo methods were used to control for multiple comparisons; two-sided p values <3.3 × 10(-4) were statistically significant. Heterogeneity tests comparing the two most common subtypes, luminal A (n = 679) and basal-like (n = 200), were based on the Wald statistic.
  
  
  RESULTS
  ESR1 rs6914211 (AA vs. AT+TT, OR 2.24, 95 % CI 1.51-3.33), ESR1 rs985191 (CC vs. AA, OR 2.11, 95 % CI 1.43-3.13), and PGR rs1824128 (TT+GT vs. GG, OR 1.33, 95 % CI 1.14-1.55) were associated with risk after accounting for multiple comparisons. Rs6914211 and rs985191 were in strong linkage disequilibrium among controls (African-Americans r (2) = 0.70; whites r (2) = 0.95). There was no evidence of heterogeneity between luminal A and basal-like subtypes, and the three SNPs were also associated with elevated risk of the less common luminal B, HER2+/ER-, and unclassified subtypes.
  
  
  CONCLUSIONS
  ESR1 and PGR SNPs were associated with risk, but lack of heterogeneity between subtypes suggests variants in hormone-related genes may play similar roles in the etiology of breast cancer molecular subtypes.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA, nyantesj@mail.nih.gov.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Nyante
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
authors.forename: Jay S
authors.initials: JS
authors.lastname: Kaufman
authors.forename: Jeannette T
authors.initials: JT
authors.lastname: Bensen
authors.forename: Dan Yu
authors.initials: DY
authors.lastname: Lin
authors.forename: Jill S
authors.initials: JS
authors.lastname: Barnholtz-Sloan
authors.forename: Yijuan
authors.initials: Y
authors.lastname: Hu
authors.forename: Qianchuan
authors.initials: Q
authors.lastname: He
authors.forename: Jingchun
authors.initials: J
authors.lastname: Luo
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D004967:Estrogens / Q000235:genetics*; D005006:Ethnicity; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D009657:North Carolina / Q000453:epidemiology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011374:Progesterone / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D055815:Young Adult
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D012738:Sex Hormone-Binding Globulin; D011374:Progesterone