Despite the fact that the exact mechanism underlying the curcumin-mediated regulation of SKP2 is not fully understood, the present study illuminated the fact that the PI3K/Akt-SKP2 pathway functioned differentially in response to curcumin in the two breast cancer subtypes and that the ability of curcumin to inactivate SKP2-dependent signaling was impaired by the continuous Akt phosphorylation in the curcumin-resistant MCF-7 cells, suggesting that the co-administration of curcumin and PI3K- and/ or SKP2-targeted inhibitors may be better alternatives in clinical practice. Here, SKP2 is linked to breast cancer.