Epidemiology Estrogen metabolizing polymorphisms and breast cancer risk among older white women Francesmary Modugno 1,2 , Joseph M. Zmuda 1 , Douglas Potter 2,3 , Chao Cai 2 , Elad Ziv 4 , Steven R. Cummings 5 , Katie L. Stone 4 , Phillip A. Morin 6 , Deborah Greene 7 , and Jane A. Cauley 1 1 Department of Epidemiology, Graduate School of Public Health; 2 University of Pittsburgh Cancer Institute; 3 Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; 4 University of California (San Francisco), Department of Medicine, San Francisco, CA, USA; 5 California Pacific Medical Center Research Institute, Director of Clinical Research, San Francisco Coordinating Center, San Francisco, CA, USA; 6 Axys Pharmaceuticals, Inc. San Francisco, CA, Southwest Fisheries Science Center, La Jolla, CA, USA; 7 Roche Molecular Systems, Pleasanton, CA, USA Key words: breast neoplasms, epidemiology, estrogen metabolism, genetic polymorphisms, prospective cohort study Summary Objective. To investigate breast cancer risk according to metabolizing genes polymorphisms in older women. Methods. A subset (43.8%) of 4248 older, white women from the Study of Osteoporotic Fractures (SOF) were genotyped for the catechol-O-methyltransferase (COMT) Val108Met polymorphism and the CYP1A1*2C locus. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between genotypes and breast cancer while controlling for potential confounders. Results. During a mean follow up of 12.4 years, 252 women (5.9%) developed breast cancer. The HR (95% CI) for breast cancer was 1.24 (0.87–1.75) for COMT Val/Met and 1.35 (0.93–1.97) for COMT Met/Met . No interactions with lifestyle and reproductive factors were found. The HR associated with the CYP1A1*2C Val allele was 0.80 (0.46, 1.39) with little evidence for interactions with lifestyle or reproductive factors. Conclusions. Among older white women, neither the COMT Val108/158Met polymorphism nor the CYP1A*2C Val allele plays a major role in breast cancer risk either alone or in combination with lifestyle and reproductive factors. Introduction Estrogen is believed to be a causal factor in postmeno- pausal breast cancer [1,2]. Catechol metabolites of estrogen may be causal as well [3–7]. Catechol estrogens are produced by the hydroxylation of the parent estro- gen at the aromatic A ring [8]. In the breast, CYP1A1 is responsible for the 2-hydroxylation of estrogens, whereas CYP1B1 is responsible for 4-hydroxylation [9]. Both the 2- and 4-OH metabolites can be inactivated by glucuronidation [10], sulfation [10], or methylation [4,6], although O-methylation catalyzed by COMT is quan- titatively the most active conjugation pathway for the catechol estrogens [9]. While the 4-hydroxy metabolites have been associated with carcinogenesis, the 2-OH products have not [3]. Indeed, the 2-OH pathway may be anti-carcinogenic [11]. In several [12–18], but not all [19–21] epidemiologic studies, higher levels of 2-OH are associated with reduced breast cancer risk. Thus, factors favoring the production of 2-OH metabolites as well as those favoring the inactivation of 4-OH metabolites may impact breast cancer risk. Recent attention has focused on polymorphisms in genes involved in estrogen metabolism as potential breast cancer risk modifying factors (reviewed by Mitrunen [9]). Several functionally active polymor- phisms in these genes have been reported. Among them is a G to A transition in Exon 4 of COMT, which results in a valine to methionine substitution at codon 108/158 of the cytosolic/membrane-bound form of the protein [22,23], and an A to G substitution in Exon 7 of CYP1A1, which results in an amino acid change as well (Ile462Val) [24]. Both of these polymorphisms have been associated with altered enzyme activity. The COMT Met allele encodes a variant that is heat sensitive and is associated with a 2- to 4-fold decrease in catalytic activity among homozygotes [25,26]. In contrast, the CYP1A1*2C Val allele is associated with higher enzyme activity [27]. Despite changes in enzyme activity and despite sup- port from animal models suggesting that these two polymorphisms would modify breast cancer risk, the results to date have been equivocal. Five studies [28–32] of the CYP1A1*2C allele have reported no significant Breast Cancer Research and Treatment (2005) 93: 261–270 Ó Springer 2005 DOI 10.1007/s10549-005-5347-8