URSOLIC ACID INHIBITED PROLIFERATION AND INVASION OF MDA-MB-231 HUMAN BREAST CANCER CELLS VIA REGULATING CELLULAR SIGNAL TRANSDUCTION PATHWAYS

Breast cancer is the most common cancer and the second leading cause of cancer death among American women. Increased intake of fruits and vegetables has been suggested to be one of major dietary factors reducing the risk of breast cancer. The health benefits were largely attributed to phytochemicals in fruits and vegetables. Ursolic acid (UA), a widely-distributed triterpenoid in fruits, vegetables, herbs, and spices, has been reported to have anti-cancer activities. However, its mechanism of actions against breast cancer remain unclear. The hypothesis of this study is that UA inhibits proliferation and invasion of MDA-MB-231 human breast cancer cells via regulating cellular signal transduction pathways. Specific objectives are designed as: a) to investigate anti-proliferation and anti-invasion effects of UA in MDA-MB-231 human breast cancer cells; b) To determine specific molecular targets of UA on cellular signal transduction pathways in MDA-MB-231 human breast cancer cells; and c) to investigate potential synergistic effects of combining ursolic acid with paclitaxel toward breast cancer proliferation. UA significantly inhibited proliferation of MDA-MDB-231 human breast cancer cells in a dose-dependent manner at the concentrations without cytotoxicity. The EC50 value of anti-proliferative activity was 30.67 µM. UA at concentrations of 20, 30, and 40 µM significantly inhibited cell invasion. Additional tests associated anti-invasion activity of UA with antagonizing the stimulation of EGF. UA affected 8 targeted proteins in cellular signaling pathway in primary signaling screening. Akt, mTOR and MAPK signaling pathways were involved. Western blots indicated UA significantly downregulated EGF-induced EGFR phosphorylation, which was correlated with reported inhibitory effects of UA on EGF-induced invasion. UA inhibited JAK/STAT3 and Akt activation, and downregulated NF-κB expression and activation. UA, paclitaxel and their combination significantly inhibited proliferation of MDA-MB-231 and MCF7 breast cancer cells in a dose-dependent manner. Synergistic effect was observed at 95% inhibition rate in MDA-MB-231 breast cancer cells and at 50% inhibition rate in MCF7 cells. We demonstrated that UA exhibited inhibitory activity toward proliferation and invasion of MDA-MB-231 cells via regulating cell signaling pathways. These data shed light on understanding the protective activity of plant foods against breast cancer