Tamoxifen, flaxseed and the lignan enterolactone increase stroma and cancer cell derived IL-1Ra and decrease tumor angiogenesis in estrogen dependent breast cancer

The proinflammatory cytokines IL-1α and IL-1β promote tumor angiogenesis, which might be counteracted by the IL-1 receptor antagonist (IL-1Ra) anakinra, a clinically approved agent. A diet with high amounts of phytoestrogens such as flaxseed (Flax), genistein (GEN), and the mammalian lignan enterolactone (ENL) may affect breast cancer progression in a similar fashion as the anti-estrogen tamoxifen. Both cancer cells and tumor stroma may be targets for cancer therapy. By using microdialysis in a model of human breast cancers in nude mice, we could perform species-specific analyses of released proteins in the microenvironment. We show that tumors 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. Cancer cell released IL-1Ra were approximately five times higher compared with stroma derived IL-1Ra. Tamoxifen, Flax, and ENL increased IL-1Ra levels significantly whereas GEN did not. The tumor stroma contained macrophages, which expressed the estrogen receptor. In vitro, estradiol decreased IL-1Ra released from breast cancer cells and from cultured macrophages. IL-1Ra decreased endothelial cell proliferation significantly in vitro while breast cancer cell proliferation was unaffected by estradiol. Finally, IL-1Ra therapy of tumor-bearing mice opposed estrogen dependent breast cancer growth and decreased angiogenesis. We conclude that the release of IL-1s both by cancer cells and the stroma, where macrophages are one key component, may offer feasible targets for anti-estrogen therapy and dietary interventions against breast cancer. (Author's abstract)