Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Cancer Epidemiology/Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, Hamburg, Germany.
Int J Cancer. 2018 Dec 1;143(11):2698-2708. doi: 10.1002/ijc.31647. Epub 2018 Sep 29.
Higher lignan exposure has been associated with lower all-cause mortality (ACM) and breast cancer-specific mortality (BCSM) for postmenopausal breast cancer patients. However, the biological mechanisms underpinning these associations are still unclear. We investigated for the first time whether and to what extent the association between enterolactone (ENL), the major lignan metabolite, and postmenopausal breast cancer prognosis is mediated by inflammatory biomarkers. Circulating concentrations of ENL and inflammatory markers were measured in a population-based prospective cohort of 1,743 breast cancer patients recruited between 2002 and 2005 and followed-up until 2009. Hazard ratios (HR) and 95% CIs were estimated using multivariable Cox regression. Mediation analysis was performed to estimate the percentage association between ENL (log2) and ACM, BCSM and distant disease-free survival (DDFS), which is mediated by C-reactive protein (CRP) (log2), as the strongest potential mediator, and also interleukin (IL)-10. Median serum/plasma ENL and CRP concentrations for all patients, including 180 deceased patients, were 23.2 and 17.5 nmol/L, and 3.2 and 6.5 mg/l, respectively. ENL concentrations were significantly inversely associated with ACM, BCSM and DDFS (per doubling of ENL concentrations: HRs 0.93 [0.87, 0.99], 0.91 [0.84, 0.99] and 0.92 [0.87, 0.99]), after adjusting for prognostic factors and BMI. Estimated 18, 14 and 12% of the effects of ENL on ACM, BCSM and DDFS, respectively, were mediated through CRP. No mediational effect of IL-10 was found. We provide first evidence that the proinflammatory marker CRP may partially mediate the association of ENL with postmenopausal breast cancer survival, which supports hormone-independent mechanisms.
较高的木质素摄入量与绝经后乳腺癌患者的全因死亡率（ACM）和乳腺癌特异性死亡率（BCSM）降低有关。然而，这些关联背后的生物学机制仍不清楚。我们首次研究了肠内酯（ENL），木质素的主要代谢物，与绝经后乳腺癌预后之间的关联是否以及在何种程度上受炎症生物标志物的影响。在 2002 年至 2005 年间招募并随访至 2009 年的一项基于人群的前瞻性队列研究中，测量了 1743 名乳腺癌患者的循环 ENL 和炎症标志物浓度。使用多变量 Cox 回归估计风险比（HR）和 95%置信区间。进行中介分析以估计 ENL（log2）与 ACM、BCSM 和远处无病生存（DDFS）之间的关联百分比，CRP（log2）作为最强的潜在中介物，以及白细胞介素（IL）-10。所有患者（包括 180 名死亡患者）的血清/血浆 ENL 和 CRP 中位数浓度分别为 23.2 和 17.5 nmol/L 和 3.2 和 6.5 mg/L。在调整预后因素和 BMI 后，ENL 浓度与 ACM、BCSM 和 DDFS 呈显著负相关（ENL 浓度每增加一倍：HRs 0.93 [0.87, 0.99]、0.91 [0.84, 0.99] 和 0.92 [0.87, 0.99]）。CRP 介导了 ENL 对 ACM、BCSM 和 DDFS 影响的 18%、14%和 12%。未发现 IL-10 的中介作用。我们首次提供证据表明，促炎标志物 CRP 可能部分介导了 ENL 与绝经后乳腺癌生存之间的关联，这支持了激素非依赖性机制。
