Abstract P2-05-28: The impact of the plant lignin secoisolariciresinol diglycoside on preclinical models of estrogen receptor positive breast cancer
Authors: Bowers LW , Ford NA , Rossi EL , Shamsunder MG , Kimler BF , Fabian CJ , Hursting SD 
Published: May 2016

Abstract
Background: Several preclinical studies indicate that secoisolariciresinol diglycoside (SDG), a polyphenolic plant lignin found most abundantly in flaxseeds, inhibits the progression of both estrogen receptor (ER) positive and negative mammary tumors. SDG is metabolized by gut bacteria into the biologically active metabolites enterolactone (ENL) and enterodiol (END), which are known to have anti-estrogenic activity. However, the mechanisms mediating SDG's anti-tumor effects remain poorly understood.
Methods: In a dose-determination pilot study linked to an ongoing clinical trial of SDG in women at high risk for breast cancer, 18 week old C57BL/6 mice were randomized to a control diet or SDG-supplemented diets (25 or 74 mg/kg of food) for 8 weeks prior to euthanization, and the levels of serum and tissue SDG metabolites (particularly ENL and END), metabolic hormones and inflammatory markers were measured. In an ongoing tumor study, 12-week old C57BL/6 and foxn1 nu/nu mice were randomized to the control or control plus SDG (100 mg/kg of food, a dose projected to match ENL and END metabolite levels achieved in the clinical trial) diet regimen. After 8 weeks on diet, they will receive orthotopic injections of E0771 mouse mammary tumor cells or BT-483 human breast cancer cells (both ER positive), continuing on the same diets until euthanization. Cell culture studies examining the impact of biologically relevant concentrations of ENL and END on E0771 and BT-483 cells are also in progress.
Results: In comparison to those maintained on the control diet, the higher dose SDG diet reduced estrogen and pro-inflammatory signaling in the pilot study mice, as evidenced by higher interleukin 10 and lower C-reactive protein mammary fat pad expression as well as lower circulating levels of the adipokines leptin and resistin, which have been linked to chronic inflammation. High dose SDG also decreased serum insulin and glucose levels, indicating improved metabolic function. Because serum ENL and END levels in the pilot study did not reach those achieved in the SDG clinical trial, a 100 mg/kg SDG dose was chosen for the tumor study. Cell culture studies indicate that ENL (150 nM) inhibits E0771 and BT-483 cell proliferation and ER alpha:beta expression ratio.
Conclusions: Preliminary data suggests that the anti-tumor effects of SDG's metabolites may be mediated through multiple mechanisms, including improvements in metabolic function and inflammatory signaling as well as modulation of breast cancer cell gene expression. The results of the ongoing tumor study will inform the design of additional cell culture studies aimed at further defining these mechanisms.
Citation Format: Bowers LW, Ford NA, Rossi EL, Shamsunder MG, Kimler BF, Fabian CJ, Hursting SD. The impact of the plant lignin secoisolariciresinol diglycoside on preclinical models of estrogen receptor positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-28.