title: Polymorphisms in steroid hormone pathway genes and mammographic density.
abstract: Mammographic density has been linked with exposure to endogenous and exogenous steroid hormones, and increased breast cancer risk. Variation in breast density may be due, in part, to polymorphisms in steroid hormone biosynthesis, metabolism and signaling genes. We conducted cross-sectional analyses within the Nurses' Health Study (n = 538), to investigate variation in mammographic breast density, by 10 polymorphisms in eight candidate genes (CYP17, CYP19, CYP1A1, CYP1B1, COMT, UGT1A1, AR, and AIB1). Breast density was assessed using a computer-assisted technique. We evaluated whether associations between variant alleles of these genes and breast density differed by menopause and postmenopausal hormone (PMH) use. Polymorphisms in CYP17, CYP19, CYP1B1, COMT CYP1A1, or AR were not associated consistently with breast density among premenopausal or postmenopausal women. Premenopausal women with the 7/7 UGT1A1 genotype had lower breast density (difference compared to the 6/6 genotype of: -16.5% density; p = 0.04). In contrast, postmenopausal women with the 7/7 UGT1A1 genotype had greater breast density compared to those with the 6/6 genotype (+6.2% density; p = 0.05); this association was strongest among current PMH users (+13.0% density; p = 0.03). In analyses limited to postmenopausal women, breast density was also greater among women carrying short AIB1 alleles (< or = 26 glutamine repeats; +4.1% density; p = 0.04). Most of the variants in the candidate breast cancer genes evaluated in this study are not strong predictors of breast density. However, our findings of differences in associations for UGT1A1 and AIB1 genotypes with breast density by menopausal status needs additional corroboration.
authors.affiliation: Department of Epidemiology, Harvard School of Public Health Boston, MA, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hankinson
authors.forename: Immaculata
authors.initials: I
authors.lastname: De Vivo
authors.forename: Chantal
authors.initials: C
authors.lastname: Guillemette
authors.forename: Naoko
authors.initials: N
authors.lastname: Ishibe
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Celia
authors.initials: C
authors.lastname: Byrne
mesh_terms: D000328:Adult; D000368:Aged; D001141:Aromatase / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D015914:Estrogen Replacement Therapy; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006728:Hormones / Q000235:genetics*; D006801:Humans; D008327:Mammography; D008593:Menopause; D008780:Methyltransferases / Q000235:genetics; D008875:Middle Aged; D056921:Nuclear Receptor Coactivator 3; D011110:Polymorphism, Genetic; D011944:Receptors, Androgen / Q000235:genetics; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D001141:Aromatase; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D014453:Glucuronosyltransferase; D006728:Hormones; D008780:Methyltransferases; D056921:Nuclear Receptor Coactivator 3; D011944:Receptors, Androgen; D013254:Steroid 17-alpha-Hydroxylase; D014157:Transcription Factors; D000099148:UGT1A1 Enzyme; C585496:CYP1B1 protein, human; C019608:caffeate O-methyltransferase