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

摘要

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. As proposed in Specific Aim 1, we have shown that dependent on estrogen receptor (ER) status, E2 and resveratrol have differential effects on Rac activity, cell migration/invasion, and cell growth. In the ER beta +ve MDAMB- 231 breast cancer cell line, 5 M resveratrol, a low physiological concentration, decreased cell proliferation, caused cell cycle arrest at G2/S phase but increased migration and invasion as well as Rac activity. In the ER ve MDA-MB-435 breast cancer cell line, 5 M resveratrol did not affect cell growth and cell cycle progression but increased cell migration/invasion. As proposed in Specific Aim 2, we tested the effect of different resveratrol concentrations on mammary tumor growth and metastasis. Our results show that at all concentrations tested, resveratrol increased mammary tumor growth and metastasis. Interestingly, tumors from mice that received resveratrol diets (0.5, 5, and 50mg/kg body weight) exhibited enhanced Rac activity. However, tumor growth or migration/invasion of this cell line could not be inhibited by a commercially available Rac inhibitor NSC-23766. Therefore, we are developing novel Rac inhibitors as anti breast cancer metastasis compounds (Hernandez, et al., submitted). Even though resveratrol alone is limited in use as a breast cancer metastasis preventive, resveratrol in combination with other grape polyphenols reduced breast cancer growth and metastasis to bone and liver (Castillo- Pichardo et al., 2009).