Estrogen Metabolism and Risk of Breast Cancer in Postmenopausal Women
Estrogen Metabolism and Risk of Breast Cancer in Postmenopausal Women
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DOI：
10.1093/jnci/djr531
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发表时间：
2012-02-01
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影响因子：
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通讯作者：
Ziegler, Regina G.
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作者：
Fuhrman, Barbara J.;Schairer, Catherine;Ziegler, Regina G.
背景雌激素是公认的乳腺癌的致病因素。雌激素代谢的个体间差异也可能影响乳腺癌的风险，并可能为乳腺癌发生机制提供线索。长期存在的假说雌激素代谢可能会影响乳腺癌还没有得到充分的流行病学研究，因为缺乏准确的，可重复的，高通量的测定雌激素代谢产物。方法我们进行了一项前瞻性的病例对照研究嵌套在前列腺，肺，结直肠和卵巢癌筛查试验（PLCO）。参与者包括277名发生浸润性乳腺癌的女性（病例受试者）和423名匹配的对照受试者;在PLCO基线时，所有受试者年龄为55-74岁，绝经后且未使用激素治疗，并提供血液样本。采用液相色谱-串联质谱法测定了15种雌激素和雌激素代谢物的血清浓度，包括母体雌激素、雌酮和雌二醇，以及类固醇环C-2、C-4或C-16位不可逆羟基化途径中的雌激素代谢物。我们使用多变量考克斯比例风险模型计算了单个雌激素和雌激素代谢物、按代谢途径分组的雌激素和雌激素代谢物的最高与最低十分位数风险的近似风险比（HR）以及代谢途径比。结果几乎所有雌激素、雌激素代谢产物和代谢途径组均与乳腺癌风险增加相关;血清中未结合雌二醇浓度与乳腺癌风险密切相关（HR = 2.07，95%可信区间[CI] = 1.19 ~ 3.62）。在调整非结合雌二醇后，没有雌激素、雌激素代谢物或代谢途径组与乳腺癌风险保持统计学显著相关。2-羟基化途径与母体雌激素的比例（HR = 0.66，95% CI = 0.51 - 0.87）和4-羟基化途径儿茶酚与4-羟基化途径甲基化儿茶酚的比值（HR = 1.34，95% CI = 1.04至1.72）在统计学上与乳腺癌的风险显著相关，并且在调整非结合雌二醇后仍然如此。母体雌激素的广泛2-羟基化与较低的风险相关，而潜在遗传毒性的4-羟基化途径儿茶酚的不太广泛的甲基化与绝经后乳腺癌的较高风险相关。
Background Estrogens are recognized causal factors in breast cancer. Interindividual variation in estrogen metabolism may also influence the risk of breast cancer and could provide clues to mechanisms of breast carcinogenesis. Long-standing hypotheses about how estrogen metabolism might influence breast cancer have not been adequately evaluated in epidemiological studies because of the lack of accurate, reproducible, and high-throughput assays for estrogen metabolites.Methods We conducted a prospective case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants included 277 women who developed invasive breast cancer (case subjects) and 423 matched control subjects; at PLCO baseline, all subjects were aged 55-74 years, postmenopausal and not using hormone therapy, and provided a blood sample. Liquid chromatography-tandem mass spectrometry was used to measure serum concentrations of 15 estrogens and estrogen metabolites, in unconjugated and conjugated forms, including the parent estrogens, estrone and estradiol, and estrogen metabolites in pathways defined by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring. We calculated hazard ratios (HRs) approximating risk in highest vs lowest deciles of individual estrogens and estrogen metabolites, estrogens and estrogen metabolites grouped by metabolic pathways, and metabolic pathway ratios using multivariable Cox proportional hazards models. All statistical tests were two-sided.Results Nearly all estrogens, estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No estrogen, estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol.Conclusions More extensive 2-hydroxylation of parent estrogens is associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with higher risk of postmenopausal breast cancer.