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

Our hypothesis is 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 proposed to test the effect of E2, resveratrol, or a small molecule Rac-specific inhibitor NSC23766 on Rac activity, cell migrationinvasion, and cell cycle progression of metastatic breast cancer cells. We show that dependent on estrogen receptor ER status, E2 and resveratrol have differential effects on Rac activity, cell migrationinvasion, and cell growth. The Rac inhibitor NSC23766 only had a modest inhibitory effect on Rac activity or cell migration of breast cancer cell lines. Therefore, we developed novel derivatives of NSC-223766 and show that EHop-017 and EHop-023 are more efficient inhibitors of Rac activity and cell migration than NSC-23766. EHop-023 also inhibits mammary tumor growth in vivo. Aim 2 proposed 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. Our studies show that at low concentrations, resveratrol alone did not affect breast cancer progression. Interestingly, resveratrol in combination with other grape polyphenols reduced breast cancer growth and metastasis to bone and liver Castillo-Pichardo et al., 2009. Therefore, E2 and low concentrations of resveratrol promote while high concentrations of resveratrol inhibit breast cancer progression in a breast cancer cell line that express ER . However, in the ER - cell line, estrogen had no effect on Rac activity or cell invasion while resveratrol was inhibitory at all concentrations tested.