Sampson Joshua N, Falk Roni T, Schairer Catherine, Moore Steven C, Fuhrman Barbara J, Dallal Cher M, Bauer Douglas C, Dorgan Joanne F, Shu Xiao-Ou, Zheng Wei, Brinton Louise A, Gail Mitchell H, Ziegler Regina G, Xu Xia, Hoover Robert N, Gierach Gretchen L
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
University of Arkansas for Medical Sciences, Fay W. Boozman College of Public Health, Little Rock, Arkansas.
Cancer Res. 2017 Feb 15;77(4):918-925. doi: 10.1158/0008-5472.CAN-16-1717. Epub 2016 Dec 23.
Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation:16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies. .
内源性雌二醇和雌酮与乳腺癌风险增加存在因果关系。在本研究中，我们评估了关于这些母体雌激素的代谢如何影响风险的多种相互竞争的假设。在四个不同的患者队列中，对1298例绝经后乳腺癌病例和1524例匹配对照的雌二醇、雌酮及13种代谢物的诊断前浓度进行了测量。各队列中样本采集与诊断之间的中位时间为4.4至12.7年。通过液相色谱 - 串联质谱法测定血清或尿液中的雌激素分析物。总雌激素水平（将所有15种雌激素/雌激素代谢物相加）与乳腺癌风险呈强烈正相关。在对总雌激素水平进行标准化后，我们还发现2 - 羟基化途径代谢物水平的相对增加，或2 - 羟基化:16 - 羟基化途径代谢物的比例增加，与乳腺癌风险呈负相关。这些关联因总雌激素水平而异，在最高三分位数的女性中风险降低幅度最大。经过适当验证后，这些发现提示了通过生活方式改变或化学预防策略来改变个体雌激素代谢谱从而预防乳腺癌的机会。
