The present study further explored the idea that the distinct behavior of the PI3K/Akt-SKP2 signaling pathway in response to curcumin was highly associated with the differential susceptibilities of MCF-7 and MDA-MB-231 cells to the cytotoxic effects of curcumin, in which the levels of Akt phosphorylation was an important factor influencing its ability to determine the activity of SKP2 and thereby affected the responses of the breast cancer cells to curcumin. The gene discussed is SKP2; the disease is breast cancer.