![]() Although there is limited epidemiologic data for premenopausal women, among premenopausal women in the Nurses' Health Study II (NHSII), urinary mid-luteal levels of one 16-pathway EM and a higher ratio of 16-pathway metabolites to parent estrogens were associated with increased risk of breast cancer, while metabolites in the 2- and 4-pathways appeared inversely associated with risk ( 17). Animal and laboratory evidence have demonstrated that metabolites in the 16-pathway are not only genotoxic, causing the formation of depurinating DNA adducts, but also bind tightly to the estrogen receptor, upregulate it, and increase cell proliferation ( 14–16). Laboratory studies suggest that 4-pathway catechols have more potential to induce DNA damage than 2-pathway catechols because they form covalent, depurinating adducts, and 2-methoxyestradiol may have antiestrogenic properties, inhibiting proliferation of breast cancer cells. Quinones may damage DNA directly, and also may undergo redox cycling to produce mutagenic reactive oxygen species. Catechol estrogens, which have two adjacent hydroxyl groups, are formed after the initial hydroxylation of the parent estrogens at the 2- or 4-positions and may be oxidized to produce reactive quinones or inactivated by methylation of one of the adjacent their hydroxyl groups. Estrogen metabolites (EM) formed in each pathway are believed to have varying degrees of carcinogenic potential ( 13). Parent estrogens, estrone and estradiol, are irreversibly metabolized along three different pathways, depending on the initial hydroxylation at the 2-, 4-, or 16-position of the steroid ring. Caffeine represents a particularly interesting biologic component of coffee with respect to breast cancer, given that enzymes involved in its metabolism also play a role in estrogen metabolism ( 11, 12). Coffee contains polyphenol antioxidants, which have been hypothesized to reduce breast cancer risk ( 9, 10), and is a major dietary source of caffeine, which has been inversely associated with breast cancer risk in some ( 1, 2, 7), though not all ( 3–6), studies. Isolating the mechanism through which coffee might affect cancer risk is complicated by the chemical complexity of coffee, which comprises many potentially bioactive compounds. ![]() Two meta-analyses reported that a 2-cup/day increase in coffee intake was associated with a nonsignificant 2% lower breast cancer risk ( 7, 8). Although some evidence suggests a small inverse association between coffee and breast cancer risk ( 1, 2), some large prospective studies have reported null associations ( 3–6). ©2015 AACR.ĭespite investigation in many large-scale epidemiologic studies, the association between coffee and breast cancer risk remains unclear. Cancer Epidemiol Biomarkers Prev 24(8) 1174–83. ![]() Impact: Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism. ![]() Tea intake was positively associated with 17-epiestriol (52% difference P trend = 0.01).Ĭonclusion: Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women. ≤1–3 cups/month) had significantly lower levels of two 16-pathway metabolites, estriol (25% difference P trend = 0.01) and 17-epiestriol (48% difference P trend = 0.0004). lowest) category of intake (≥2 cups/day vs. Decaffeinated coffee was not associated with 2-pathway metabolism, but women in the highest (vs. ≤6 cups/week P trend = 0.001) and 2-hydroxyestrone (52% difference P trend = 0.001), and several ratio measures. Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, ≥4 cups/day vs. Results: Compared with women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16α-hydroxyestrone (28% difference P trend = 0.01) and 16-epiestriol (13% difference P trend = 0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio ( P trend = 0.03). Multivariate linear mixed models were used to estimate geometric means of individual EM, pathways, and ratios by intake categories, and P values for tests of linear trend. Methods: High-performance liquid chromatography/tandem mass spectrometry was used to quantify levels of 15 individual estrogens and estrogen metabolites (EM) among 587 premenopausal women in the Nurses' Health Study II with mid-luteal phase urine samples and caffeine, coffee, and/or tea intakes from self-reported food frequency questionnaires. Background: Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones. ![]()
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