Department of Nutrition, University of North Carolina, 135 Dauer Drive, CB #7461, Chapel Hill, NC, 27599, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina, 450 West Drive, Chapel Hill, NC, 27514, USA.
Breast Cancer Res Treat. 2019 Feb;173(3):545-557. doi: 10.1007/s10549-018-5021-6. Epub 2018 Oct 26.
Exposure to the polyphenolic plant lignan secoisolariciresinol diglucoside (SDG) and its metabolite enterolactone (ENL) has been associated with reduced breast cancer progression, particularly for estrogen receptor alpha (ERα)-negative disease, and decreased preclinical mammary tumor growth. However, while preclinical studies have established that SDG and ENL affect measures of progression in models of triple-negative breast cancer (TNBC, a subset of ERα-negative disease), the molecular mechanisms underlying these effects remain unclear.
C57BL/6 mice were fed a control diet (control, 10% kcal from fat) or control diet + SDG (SDG, 100 mg/kg diet) for 8 weeks, then orthotopically injected with syngeneic E0771 mammary tumor cells (a model of TNBC); tumor growth was monitored for 3 weeks. The role of reduced NF-κB signaling in SDG's anti-tumor effects was explored in vitro via treatment with the bioactive SDG metabolite ENL. In addition to the murine E0771 cells, the in vitro studies utilized MDA-MB-231 and MCF-7 cells, two human cell lines which model the triple-negative and luminal A breast cancer subtypes, respectively.
SDG supplementation in the mice significantly reduced tumor volume and expression of phospho-p65 and NF-κB target genes (P < 0.05). Markers of macrophage infiltration were decreased in the distal-to-tumor mammary fat pad of mice supplemented with SDG relative to control mice (P < 0.05). In vitro, ENL treatment inhibited viability, survival, and NF-κB activity and target gene expression in E0771, MDA-MB-231, and MCF-7 cells (P < 0.05). Overexpression of Rela attenuated ENL's inhibition of E0771 cell viability and survival.
SDG reduces tumor growth in the E0771 model of TNBC, likely via a mechanism involving inhibition of NF-κB activity. SDG could serve as a practical and effective adjuvant treatment to reduce recurrence, but greater understanding of its effects is needed to inform the development of more targeted recommendations for its use.
暴露于多酚植物木脂素 secoisolariciresinol 二葡萄糖苷（SDG）及其代谢物肠内酯（ENL）与乳腺癌进展减少相关，特别是对于雌激素受体 alpha（ERα）阴性疾病，以及临床前乳腺肿瘤生长减少。然而，虽然临床前研究已经确定 SDG 和 ENL 影响三阴性乳腺癌（TNBC，ERα 阴性疾病的一个亚组）模型中进展的措施，但这些作用的分子机制仍不清楚。
C57BL/6 小鼠喂食对照饮食（对照，10%脂肪热量）或对照饮食+SDG（SDG，饮食 100mg/kg）8 周，然后同源注射同源 E0771 乳腺肿瘤细胞（TNBC 模型）；监测肿瘤生长 3 周。通过用生物活性 SDG 代谢物 ENL 处理，在体外探索 NF-κB 信号降低在 SDG 抗肿瘤作用中的作用。除了小鼠 E0771 细胞外，体外研究还利用 MDA-MB-231 和 MCF-7 细胞，这两种细胞系分别模拟三阴性和 luminal A 乳腺癌亚型。
SDG 补充剂显著降低了肿瘤体积和磷酸化 p65 和 NF-κB 靶基因的表达（P<0.05）。与对照小鼠相比，SDG 补充剂的肿瘤远端乳腺脂肪垫中的巨噬细胞浸润标志物减少（P<0.05）。在体外，ENL 处理抑制了 E0771、MDA-MB-231 和 MCF-7 细胞的活力、存活和 NF-κB 活性和靶基因表达（P<0.05）。Rela 的过表达减弱了 ENL 对 E0771 细胞活力和存活的抑制作用。
SDG 降低了 E0771 TNBC 模型中的肿瘤生长，可能通过抑制 NF-κB 活性的机制。SDG 可作为一种实用有效的辅助治疗方法，以减少复发，但需要进一步了解其作用，以提供更有针对性的使用建议。
