Skp2 is a promising therapeutic target in breast cancer

Abstract

Breast cancer is the most common type of cancer among American women, and remains the second leading cause of cancer-related death for female in the United States. It has been known that several signaling pathways and various factors play critical roles in the development and progression of breast cancer, such as estrogen receptor, Notch, PTEN, human epidermal growth factor receptor 2, PI3K/Akt, BRCA1, and BRCA2. Emerging evidence has shown that the F-box protein S-phase kinase associated protein 2 (Skp2) also plays an important role in the pathogenesis of breast cancer. Therefore, in this brief review, we summarize the novel functions of Skp2 in the pathogenesis of breast cancer. Moreover, we provide further evidence regarding the state of our knowledge toward the development of novel Skp2 inhibitors especially natural "chemopreventive agents" as targeted approach for the prevention and/or treatment of breast cancer.

Figure 1

Illustration of the SCF^skp2 complex. The SCF (Skp1–Cullin1–F-box) E3 ubiquitin ligase complex consists of four components: Skp1, Rbx1, Cullin1, and the variable F-box protein. In SCF^skp2, the F-box protein component is Skp2. Skp2 recognizes the targeted proteins and makes the ubiquitin transfer to the substrate protein by UBC (the E2 enzyme). The addition of polyubiquitin targets substrates for degradation by the 26S proteasome. The known substrates of Skp2 include p21, p27, p57, p130, Tob1, FOXO1, and c-Myc.

Figure 2

Diagram of Skp2’s cross-talks with other major signaling pathways in breast cancer. PI3K/Akt, mTOR, PPARγ, ERK, FoxP3, and IGF regulate the expression of Skp2 in the breast cancer. Chemical compounds including Skp2 inhibitors and natural agents inhibit cell growth and induce apoptosis through down-regulation of Skp2 expression in breast cancer. Skp2, S-phase kinase associated protein 2; ERK, extracellular signal-regulated kinase; IGF-1, insulin-like growth factor-1; FoxP3, forkhead box P3; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PPARγ, peroxisome proliferator-activated receptor-γ.