title: Estrogen metabolism genotypes, use of long-term hormone replacement therapy and risk of postmenopausal breast cancer.
abstract: Association between long-term hormone replacement therapy (HRT) use and increased risk of breast cancer is still under debate. Functionally relevant genetic variants within the estrogen metabolic pathway may alter exposure to exogenous sex hormones and affect the risk of postmenopausal breast cancer. We investigated the associations of common polymorphisms in 4 genes encoding key proteins of the estrogen metabolic pathway, duration of HRT use and their interactions with breast cancer risk. We studied 530 breast cancer cases and 270 controls of the same age and ethnicity participating in a case-control study of postmenopausal women. Duration of HRT use was ascertained through a postal questionnaire. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695) and MnSOD (rs4880) polymorphisms by PCR-based RFLP and TaqMan® allelic discrimination method. Adjusted odds ratios and 95% confidence intervals were calculated using logistic regression analysis. HRT use was significantly associated with decreased breast cancer risk (p<0.001). None of the polymorphisms studied was associated with breast cancer risk. A significant interaction was observed between MnSOD 47T>C and HRT use (pinteraction=0.036); the risk of breast cancer associated with long-term vs. short-term HRT use was decreased in women homozygous for the wild-type allele and increased in women with at least one variant allele of the MnSOD 47T>C polymorphism. Our results suggest that MnSOD 47T>C polymorphism in interaction with long-term HRT use may modify the risk of breast cancer.
authors.affiliation: Institute of Medical Genetics, Department of Obstetrics and Gynecology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Jasmina Ziva
authors.initials: JZ
authors.lastname: Cerne
authors.forename: Srdjan
authors.initials: S
authors.lastname: Novakovic
authors.forename: Snjezana
authors.initials: S
authors.lastname: Frkovic-Grazio
authors.forename: Maja
authors.initials: M
authors.lastname: Pohar-Perme
authors.forename: Vida
authors.initials: V
authors.lastname: Stegel
authors.forename: Ksenija
authors.initials: K
authors.lastname: Gersak
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D001943:Breast Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000096:biosynthesis / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D004967:Estrogens / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000096:biosynthesis / Q000235:genetics; D020249:Hormone Replacement Therapy / Q000009:adverse effects*; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017698:Postmenopause; D012307:Risk Factors; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004967:Estrogens; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D013482:Superoxide Dismutase; D002394:Catechol O-Methyltransferase; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi