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

Cancer Res. 2011 Jan 1;71(1):51-60. doi: 10.1158/0008-5472.CAN-10-2289. Epub 2010 Nov 19.


The proinflammatory cytokines IL-1α and IL-1β promote tumor angiogenesis that 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 antiestrogen 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 and 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 5 times higher than 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 whereas breast cancer cell proliferation was unaffected in presence of 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 a key component, may offer feasible targets for antiestrogen therapy and dietary interventions against breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / pharmacology
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Breast Neoplasms / blood supply*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Estrogen Receptor alpha / metabolism
  • Estrogens / physiology*
  • Female
  • Flax*
  • Humans
  • Immunohistochemistry
  • Interleukin 1 Receptor Antagonist Protein / metabolism*
  • Lignans / pharmacology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms, Hormone-Dependent / blood supply*
  • Neoplasms, Hormone-Dependent / pathology
  • Neovascularization, Pathologic / prevention & control*
  • Stromal Cells / drug effects*
  • Stromal Cells / metabolism
  • Tamoxifen / pharmacology*


  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor alpha
  • Estrogens
  • Interleukin 1 Receptor Antagonist Protein
  • Lignans
  • Tamoxifen
  • 4-Butyrolactone
  • 2,3-bis(3'-hydroxybenzyl)butyrolactone