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Estrogen and the Dietary Phytoestrogen Tesveratrol as Regulators of the Rho GTPase Rac in Breast Cancer Research

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Annual rept. 7 May 2007-6 May 2008

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This award proposed to test the hypothesis that estrogen E2 and low concentrations of resveratrol promote breast cancer invasion and metastasis while high concentrations of resveratrol prevent breast cancer metastasis via regulation of the signaling protein Rac. Specific Aim1 was to test the effect of varying concentrations of E2, resveratrol, or a small molecule Rac-specific inhibitor NSC23766 on cell migration, invasion, and Rac activity of metastatic breast cancer cells. Aim 2 was to test the effect of these compounds on breast cancer progression in immunocompromised nude mice from mammary tumors established from fluorescent protein-tagged breast cancer cells. This first year report shows that at low concentrations, resveratrol acted similar to E2 and activated while at high concentrations resveratrol inhibited Rac and breast cancer cell migration. As proposed, we tested the efficiency of the commercially available Rac inhibitor NSC23766 in breast cancer cells. However, NSC23766 had only a modest inhibitory effect on Rac activity or cell migration of breast cancer cell lines. Therefore, we developed and tested novel more efficacious NSC23766 derivatives that will be used for the proposed study. For Aim 2, the effect of treatment with vehicle or resveratrol on mice with GFP-MDA-MB-435 mammary tumors was determined. Primary breast cancer progression and distant metastases as analyzed by whole body and microscopic fluorescence image analysis demonstrated that resveratrol reduced lung and liver metastases. Therefore, these experiments support our hypothesis that E2 and low concentrations of resveratrol promote while high concentrations of resveratrol inhibit breast cancer progression.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research
  • Food, Food Service and Nutrition

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