Lunasin, a novel seed peptide, sensitizes human breast cancer MDA-MB-231 cells to aspirin-arrested cell cycle and induced apoptosis

Breast cancer is one of the most common tumors in women of Western countries. The high aggressiveness and therapeutic resistance of estrogen-independent breast tumors have motivated the development of new strategies for prevention and/or treatment. Combinations of two or more chemopreventive agents are currently being used to achieve greater inhibitory effects on breast cancer cells. This study reveals that both aspirin and lunasin inhibit, in a dose-dependent manner, human estrogen-independent breast cancer MDA-MB-231 cell proliferation. These compounds arrest the cell cycle in the S- and G1-phases, respectively, acting synergistically to induce apoptosis. To begin elucidating the mechanism(s) of action of these compounds, different molecular targets involved in cell cycle control, apoptosis and signal transduction have been evaluated by real-time polymerase chain reaction (RT-PCR) array. The cell growth inhibitory effect of a lunasin/aspirin combination is achieved, at least partially, by modulating the expression of genes encoding G1 and S-phase regulatory proteins. Lunasin/aspirin therapy exerts its potent pro-apoptotic effect is at least partially achieved through modulating the extrinsic-apoptosis dependent pathway. Synergistic down-regulatory effects were observed for ERBB2, AKT1, PIK3R1, FOS and JUN signaling genes, whose amplification has been reported as being responsible for breast cancer cell growth and resistance to apoptosis. Therefore, our results suggest that a combination of these two compounds is a promising strategy to prevent/treat breast cancer.