The proinflammatory cytokines IL-1α and IL-1β have been shown to promote tumor angiogenesis, which may be counteracted by the IL-1 receptor antagonist (IL-1Ra). A diet with high amounts of phytoestrogens such as flaxseed (Flax), genistein (GEN), and the mammalian lignan enterolactone (ENL) may affect breast cancer progression possibly in a similar fashion as the anti-estrogen tamoxifen. Both cancer cells and the tumor stroma may be targets for cancer therapy. Therefore, we set up a model with species-specific components of the microenvironment by establishing human breast cancers in nude mice and sampled released proteins by microdialysis. We show that tumors of mice treated with tamoxifen, fed Flax or ENL exhibited decreased in vivo release of IL-1β derived from the murine stroma and decreased microvessel density whereas dietary GEN had no effects compared to controls. Cancer cells released IL-1Ra were approximately five times higher compared with stroma derived and tamoxifen, Flax, and ENL increased these levels significantly whereas GEN did not. In vitro, estradiol decreased released IL-1Ra of breast cancer cells. ENL completely reversed this whereas tamoxifen further increased IL-1Ra levels. IL-1Ra had no effect on breast cancer cell proliferation in presence of E2 in vitro whereas endothelial cell proliferation was significantly decreased by IL-1Ra in a dose dependent manner. Finally, IL-1Ra therapy of tumor bearing mice opposed estrogen dependent breast cancer growth and decreased tumor angiogenesis. These data may provide insights into tumor-stroma mechanisms involved in estrogen effects on breast cancer progression and tamoxifen and dietary interventions against this disease.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-02-06.