The flaxseed lignan secoisolariciresinol diglucoside decreases local inflammation, suppresses NFκB signaling, and inhibits mammary tumor growth

Abstract

Purpose 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. Methods 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (10.1007/s10549-018-5021-6) contains supplementary material, which is available to authorized users.

Secoisolariciresinol Diglucoside Delays the Progression of Aging-Related Diseases and Extends the Lifespan ofCaenorhabditis elegansvia DAF-16 and HSF-1

“…Studies under various cellular and animal models have demonstrated that SDG has potent bioactivity in reducing the risk of cancer, ameliorating oxidative stress, preventing diabetes, and protecting from neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease [ 8 , 9 ]. SDG could reduce tumor growth via inhibiting the activity of nuclear factor kappa-B in murine E0771 cells (a model of triple-negative breast cancer) [ 10 ]. SDG is also a potent angiotensin-converting enzyme (ACE) inhibitor [ 11 ].…”

Randomized Phase IIB Trial of the Lignan Secoisolariciresinol Diglucoside in Premenopausal Women at Increased Risk for Development of Breast Cancer

“…Recent research suggests that much of the effect of lignans may be as a result of antiinflammatory influences, which we have not as yet adequately explored in our clinical trial specimens [55][56][57]. Indeed, our companion study in an immunocompetent mouse model of triple negative breast cancer suggested that SDG, in doses producing equivalent enterolactone and enterodiol blood levels as in our human pilot study, suppressed NFκB activation [14]. This was associated with growth suppression of triple negative breast cancer with high initial levels of NFκB.…”

“…In preclinical studies SDG significantly increased gene and protein levels of the antioxidants HO-1, GSTM1 and NQO1 [13]. SDG may also reduce NFκB pro-inflammatory signaling through inhibition of p65 phosphorylation, as we have demonstrated in a preclinical model [14]. Although NFκB is classically activated by oxidative stress and inflammatory cytokines, it can also be activated by Receptor Activator of NFκB (RANK) which in turn is upregulated via hormonal stimulation and progesterone receptor activation [15,16].…”

“…Although NFκB is classically activated by oxidative stress and inflammatory cytokines, it can also be activated by Receptor Activator of NFκB (RANK) which in turn is upregulated via hormonal stimulation and progesterone receptor activation [15,16]. Our studies of a murine basal-like breast cancer model and two human breast cancer cell lines representing ER+ Luminal A and claudin-low triple negative suggest that SDG downregulates expression of 50% of genes in the NFκB pathway array [14]. NFκB is thought to be important in immune cell infiltration into breast stroma and development of breast cancer [17,18].…”

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…Epidemiological studies have revealed that higher dietary intake of EL precursors and higher serum concentrations of EL are correlated with decreased breast cancer risk and mortality, as well as more satisfactory survival time, particularly in postmenopausal breast cancer patients. 433 In animal experiments, EL exerts its antibreast cancer functions by inhibiting NF-κB-mediated inflammation, 434 TGF-β-induced EMT, 435 and cancer cell viability. 436 Collectively, the gut microbiome potentially affects carcinogenesis through its far-reaching impacts on estrogen metabolism, energy metabolism, and the anti-tumor function of the immune system.…”