Kristen D Brantley, Regina G Ziegler, Neal E Craft, Susan E Hankinson, A Heather Eliassen
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引用次数: 0
Abstract
Background: Estradiol and estrone are well-established risk factors for postmenopausal breast cancer (BC). Experimental evidence suggests that specific estrogen metabolites, produced via irreversible hydroxylation of estrone and estradiol at the 2- or 16-position may independently influence carcinogenesis.
Methods: We performed a nested case-control study of BC (328 BC cases; 639 controls) among postmenopausal women within the Nurses' Health Study (NHS)to examine the role of estrogens and estrogen metabolites (jointly referred to as EM). Plasma concentrations of each EM (unconjugated+conjugated forms) were measured by liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression, adjusting for BC risk factors, estimated relative risks (RR) and 95% confidence intervals (CI) of BC across quintiles of individual EM, EM pathways, and pathway ratios. Associations by estrogen/progesterone receptor (ER/PR) status were analyzed by unconditional logistic regression.
Results: Estradiol and estrone were strongly associated with increased BC risk [estradiol: RRQ5v.Q1 (95% CI)=2.64 (1.64-4.26), estrone: 2.78 (1.74-4.45); both p-trends<0.001]. The 2-hydroxylation pathway was strongly associated with risk [RRQ5v.Q1=3.09 (1.81-5.27), p-trend<0.001], and remained so after adjusting for unconjugated estradiol [RRQ5v.Q1=2.23 (1.25-3.96), p-trend=0.01]. While the 16-hydroxylation pathway was modestly associated with risk [RRQ5v.Q1=1.62 (1.03-2.54), p-trend=0.01], the association was attenuated after unconjugated estradiol adjustment [RRQ5v.Q1=1.24 (0.77-1.99), p-trend=0.19]. Similar positive associations with the 2-pathway and 16-pathway were observed for ER+/PR+ and ER-/PR- tumors.
Conclusions: In this cohort of postmenopausal women, 2-hydroxylation of estrone and estradiol was associated with increased BC risk, independent of unconjugated estradiol.
Impact: These results highlight the need to revisit the role of estrogen metabolism in BC etiology and prevention.
背景：雌二醇和雌酮是绝经后乳腺癌（BC）的公认风险因素。实验证据表明，雌酮和雌二醇在 2 位或 16 位发生不可逆羟基化反应后产生的特定雌激素代谢物可能会独立影响致癌作用：我们在护士健康研究（NHS）范围内对绝经后妇女中的 BC 病例（328 例 BC 病例；639 例对照）进行了巢式病例对照研究，以探讨雌激素和雌激素代谢物（合称 EM）的作用。采用液相色谱-串联质谱法测定了每种 EM（非结合型+结合型）的血浆浓度。在对 BC 风险因素进行调整后，多变量条件逻辑回归估算了 BC 在单个 EM、EM 途径和途径比率的五分位数中的相对风险 (RR) 和 95% 置信区间 (CI)。无条件逻辑回归分析了雌激素/孕激素受体（ER/PR）状态的相关性：RRQ5v.Q1（95% CI）=2.64 (1.64-4.26)，雌酮：2.78 (1.74-4.45)；均为 p 趋势结论：在这一绝经后人群中，雌二醇和雌酮受体（ER/PR）状态与 BC 风险增加密切相关：在这组绝经后妇女中，雌酮和雌二醇的 2- 羟基化与 BC 风险的增加有关，与非结合雌二醇无关：这些结果凸显了重新审视雌激素代谢在乳腺癌病因学和预防中的作用的必要性。
期刊介绍：
Cancer Epidemiology, Biomarkers & Prevention publishes original peer-reviewed, population-based research on cancer etiology, prevention, surveillance, and survivorship. The following topics are of special interest: descriptive, analytical, and molecular epidemiology; biomarkers including assay development, validation, and application; chemoprevention and other types of prevention research in the context of descriptive and observational studies; the role of behavioral factors in cancer etiology and prevention; survivorship studies; risk factors; implementation science and cancer care delivery; and the science of cancer health disparities. Besides welcoming manuscripts that address individual subjects in any of the relevant disciplines, CEBP editors encourage the submission of manuscripts with a transdisciplinary approach.
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