Profilin-1 overexpression inhibits proliferation of MDA-MB-231 breast cancer cells partly through p27kip1 upregulation.

Profilin-1 (Pfn1), a ubiquitously expressed actin-binding protein, has gained interest in epithelial-derived cancer because of its downregulation in expression in various adenocarcinoma. Pfn1 overexpression impairs tumorigenic ability of human breast cancer xenografts thus suggesting that Pfn1 could be a tumor-suppressor protein. The objective of the present study was to determine how Pfn1 overexpression affects cell-cycle progression of breast cancer cells. We show that Pfn1 overexpression in MDA-MB-231 breast cancer cells causes cell-cycle arrest in G1 phase and dramatically reduced proliferation in culture. Pfn1 overexpression results in increased protein stability of p27(kip1) (p27-a major cyclin-dependent kinase inhibitor) and marked elevation in the overall cellular level of p27. Proliferation defect of Pfn1 overexpressers can be partly rescued by silencing p27 expression thus suggesting a critical role of p27 in Pfn1-induced growth inhibition of MDA-MB-231 cells. Finally, Pfn1 overexpression was found to sensitize MDA-MB-231 cells to apoptosis in response to cytotoxic stimulus thus suggesting for the first time that survival of breast cancer cells can also be negatively influenced by Pfn1 upregulation. These findings may provide novel insights underlying Pfn1's tumor-suppressive action. (c) 2010 Wiley-Liss, Inc.