Search

The F box protein Skp2 is oncogenic. Skp2 and Skp2B, an isoform of Skp2 are overexpressed in breast cancer. However, little is known regarding the mechanism by which Skp2B promotes the occurrence and development of breast cancer. Here, we determined the expression and clinical outcomes of Skp2 in breast cancer samples and cell lines using breast cancer database, and investigated the role of Skp2 and Skp2B in breast cancer cell growth, apoptosis and cell cycle arrest. We obtained Skp2 is significantly overexpressed in breast cancer samples and cell lines, and high Skp2 expression positively correlated with poor prognosis of breast cancer. Both Skp2 and Skp2B could promote breast cancer cell proliferation, inhibit cell apoptosis, change the cell cycle distribution and induce the increased S phase cells and therefore induce cell proliferation in breast cancer cells. Moreover, the 2 isoforms could both suppress PIG3 expression via independent pathways in the breast cancer cells. Skp2 suppressed p53 and inhibited PIG3-induced apoptosis, while Skp2B attenuated the function of PIG3 by inhibiting PHB. Our results indicate that Skp2 and Skp2B induce breast cancer cell development and progression, making Skp2 and Skp2B potential molecular targets for breast cancer therapy.

Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, has been shown to have potent antitumor effects against human breast cancer. Recent studies have shown that lapatinib upregulates p27(Kip1) (here after referred to as p27) expression and induces G₁ cell cycle arrest in various types of cancer cells. However, the regulation of p27 in lapatinib-induced cell cycle arrest is not well studied. Here we demonstrate that lapatinib-induced cell growth inhibition and G₁ cell cycle arrest in HER2-overexpressing human breast cancer cells were dependent on p27. We also show that lapatinib-induced upregulation of p27 expression was mediated through both transcriptional and post-translational mechanisms. On the one hand, lapatinib treatment led to increased FOXO3a expression and enhanced p27 transcription. On the other hand, lapatinib treatment resulted in increased DYRK1B expression, which correlated with increased p27 phosphorylation at Ser10 and decreased p27 degradation. Interestingly, we found that ERβ1 but not ERβ2 expression also upregulated p27 and enhanced lapatinib-induced cell proliferation inhibition and G₁ cell cycle arrest in HER2-overexpressing breast cancer cells. Taken together, our results suggest that lapatinib induces p27 expression via both transcriptional and post-translational upregulations, leading to cell cycle arrest and cell proliferation inhibition, and that its effect on breast cancer cells may be modified by ER expression status.