title: Polymorphisms in genes involved in sex hormone metabolism, estrogen plus progestin hormone therapy use, and risk of postmenopausal breast cancer.
abstract: Hormone therapy, estrogen plus progestin (E+P) particularly, is associated with increased risk of breast cancer. Functionally relevant polymorphisms in genes involved in sex hormone metabolism may alter exposure to exogenous sex hormones and affect risk of postmenopausal breast cancer. We evaluated associations of common polymorphisms in genes involved in estrogen and/or progesterone metabolism, E+P use, and their interactions with breast cancer risk in a case-control study of postmenopausal women (324 cases; 651 controls) nested within the VITAL cohort. None of the polymorphisms studied was, by itself, statistically significantly associated with breast cancer risk. E+P use was significantly associated with increased breast cancer risk (> or =10 years versus never; odds ratio, 1.9; 95% confidence interval, 1.3-2.8; P(trend) = 0.0002). Statistically significant interactions between CYP1A1 Ile(462)Val (P(interaction) = 0.04), CYP1A1 MspI (P(interaction) = 0.003), CYP1B1 Val(432)Leu (P(interaction) = 0.007), CYP1B1 Asn(453)Ser (P(interaction) = 0.04) and PGR Val(660)Leu (P(interaction) = 0.01), and E+P use were observed. The increased risk of breast cancer associated with E+P use was greater among women with at least one rare allele of the CYP1A1 Ile(462)Val, CYP1A1 MspI, CYP1B1 Asn(453)Ser, and PGR Val(660)Leu polymorphisms than among women homozygous for the common allele of these polymorphisms. Risk of breast cancer increased little with increasing years of E+P use among women with at least one CYP1B1 Val(432) allele; a large increase in risk was seen among women homozygous for CYP1B1 Leu(432). Our results support the hypothesis that specific polymorphisms in genes involved in sex hormone metabolism may modify the effect of E+P use on breast cancer risk.
authors.affiliation: Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center and Department of Epidemiology, University of Washington, Seattle, WA, USA. bbd3@pitt.edu
authors.forename: Brenda
authors.initials: B
authors.lastname: Diergaarde
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Eldon R
authors.initials: ER
authors.lastname: Jupe
authors.forename: Sharmila
authors.initials: S
authors.lastname: Manjeshwar
authors.forename: Craig D
authors.initials: CD
authors.lastname: Shimasaki
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Pugh
authors.forename: Daniele C
authors.initials: DC
authors.lastname: Defreese
authors.forename: Bobby A
authors.initials: BA
authors.lastname: Gramling
authors.forename: Ilonka
authors.initials: I
authors.lastname: Evans
authors.forename: Emily
authors.initials: E
authors.lastname: White
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1; D004967:Estrogens / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D020022:Genetic Predisposition to Disease; D012739:Gonadal Steroid Hormones / Q000097:blood*; D020249:Hormone Replacement Therapy / Q000009:adverse effects / Q000379:methods; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017698:Postmenopause; D015995:Prevalence; D011372:Progestins / Q000009:adverse effects / Q000627:therapeutic use*; D012189:Retrospective Studies; D012307:Risk Factors; D014861:Washington / Q000453:epidemiology
chemical_list: D004967:Estrogens; D012739:Gonadal Steroid Hormones; D011372:Progestins; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1