Abstract
PurposeExposure 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.MethodsC57BL/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.ResultsSDG 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.ConclusionsSDG 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.
Highlights
MethodsSecoisolariciresinol diglucoside (SDG) is a polyphenolic plant lignan found in flaxseeds and other oil-rich seeds and nuts as well as legumes, whole grains, certain fruits and vegetables, coffee, tea, and wine [1, 2]
The goal of this study was to establish the concentration of SDG that would result in serum ENL and END levels comparable to those achieved in a 12-month pilot clinical trial of SDG supplementation in women [27]
While the anti-tumor effects of the flaxseed lignan SDG have been thoroughly established in several models of ERα-positive breast cancer [9,10,11,12, 14,15,16,17, 35], less attention has been given to its impact on ERα-negative models, including models of basal-like and other triple-negative breast cancer subtypes, and the precise mechanisms mediating their effects
Summary
MethodsSecoisolariciresinol diglucoside (SDG) is a polyphenolic plant lignan found in flaxseeds and other oil-rich seeds and nuts as well as legumes, whole grains, certain fruits and vegetables, coffee, tea, and wine [1, 2]. To further explore SDG’s impact on breast cancer, several preclinical studies have examined the effects of lignan exposure on animal models of both pre- and postmenopausal ERα-positive breast cancer, with the vast majority demonstrating significant reductions in mammary tumor growth or preneoplastic changes [9,10,11,12,13,14,15,16,17,18]. These anti-tumor effects have been linked to decreased proliferation and angiogenesis as well as increased apoptosis [9,10,11, 13, 15,16,17]. There has been relatively little exploration of SDG’s effects on models of triple-negative breast cancer (TNBC), despite epidemiologic data suggesting enterolignans may have a stronger protective effect
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