Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide

Arsenic trioxide (As₂O₃), a component of traditional Chinese medicine, has been used successfully for the treatment of acute promyelocytic leukemia (APL), and As₂O₃ is of potential therapeutic value for the treatment of other promyelocytic malignancies and some solid tumors including breast cancer. However, the precise molecular mechanisms through which As₂O₃ induces cell cycle arrest and apoptosis in solid tumors have not been clearly understood. The goal of our study is to gain insight into the general biological processes and molecular functions that are altered by As₂O₃ treatment in MCF-7 breast cancer cells and to identify the key signaling processes that are involved in the regulation of these physiological effects. In the present study, MCF-7 cells were treated with 5 μM As₂O₃, and the differential gene expression was then analyzed by DNA microarray. The results showed that As₂O₃ treatment changed the expression level of several genes that involved in cell cycle regulation, signal transduction, and apoptosis. Notably, As₂O₃ treatment increased the mRNA and protein levels of the cell cycle inhibitory proteins, p21 and p27. Interestingly, knocking down p21 or p27 individually did not alter As₂O₃-induced apoptosis and cell cycle arrest; however, the simultaneous down-regulation of both p21 and p27 resulted in attenuating of G₁, G₂/M arrest and reduction in apoptosis, thus indicating that p21 and p27 as the primary molecular targets of As₂O₃ against breast cancer. Overall, our results provide new insights into As₂O₃-related signaling activities, which may facilitate the development of As₂O₃-based anticancer strategies and/or combination therapies against solid tumors.