The Flaxseed Lignan Secoisolariciresinol Diglucoside Decreases Local Inflammation, Suppresses NFκB Signaling, and Inhibits Mammary Tumor Growth

Breast Cancer Res Treat. 2019 Feb;173(3):545-557. doi: 10.1007/s10549-018-5021-6. Epub 2018 Oct 26.

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.

Keywords: Breast cancer; Enterodiol (END); Enterolactone (ENL); NFκB; Plant lignan; Secoisolariciresinol diglucoside (SDG).

MeSH terms

  • 4-Butyrolactone / analogs & derivatives
  • 4-Butyrolactone / blood
  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology*
  • Biomarkers
  • Butylene Glycols / administration & dosage
  • Butylene Glycols / chemistry
  • Butylene Glycols / pharmacology*
  • Cell Line, Tumor
  • Cell Survival
  • Cytokines / blood
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Flax / chemistry*
  • Gene Expression Profiling
  • Glucosides / administration & dosage
  • Glucosides / chemistry
  • Glucosides / pharmacology*
  • Immunohistochemistry
  • Lignans / blood
  • Mammary Neoplasms, Animal / drug therapy
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / metabolism*
  • Mammary Neoplasms, Animal / pathology
  • Mice
  • NF-kappa B / metabolism*
  • Signal Transduction / drug effects*

Substances

  • Anti-Inflammatory Agents
  • Biomarkers
  • Butylene Glycols
  • Cytokines
  • Glucosides
  • Lignans
  • NF-kappa B
  • 4-Butyrolactone
  • secoisolariciresinol diglucoside
  • 2,3-bis(3'-hydroxybenzyl)butyrolactone