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Oncol Rep. 2009 May;21(5):1317-22.

Simvastatin and lovastatin inhibit breast cell invasion induced by H-Ras.

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1
College of Pharmacy, Duksung Women's University, Seoul 132-714, Korea.

Abstract

Breast cancer mortality is strongly related to the invasive and metastatic potential of tumor cells. We previously showed that an active mutant of H-Ras induced invasive phenotype of MCF10A human breast epithelial cells. Membrane anchoring of Ras requires isoprenylation which involves the activity of 3-hydroxy 3-methylglutaryl (HMG)-CoA reductase. In this study, we investigated the inhibitory effect of HMG-CoA reductase inhibitors, widely used for hypercholesterolemia, on H-Ras-induced invasion of MCF10A cells. Treatment of H-Ras MCF10A cells with simvastatin and lovastatin markedly decreased isoprenylated H-Ras in membrane fraction while the unprenylated H-Ras was increased in cytosol fraction, demonstrating that these statins inhibited membrane anchoring of H-Ras in MCF10A cells. Simvastatin and lovastatin significantly inhibited H-Ras-induced invasion which was reversed by farnesyl pyrophosphate (FPP), indicating that the inhibitory effect was related to inhibition of the biosynthesis of prenylated derivatives. Statins downregulated matrix metalloproteinase (MMP)-9 and, to a lesser extent, MMP-2 in H-Ras MCF10A cells. Simvastatin and lovastatin inactivated H-Ras downstream signaling molecules, possibly by inhibiting H-Ras membrane localization and thus its function in MCF10A cells. Taken together, this study clearly demonstrated the inhibitory effect of simvastatin and lovastatin on H-Ras-induced invasion, MMP expression and signal transduction in MCF10A breast epithelial cells, providing supporting rationale for future statin trials as a therapeutic intervention to regulate breast cancer metastasis.

PMID:
19360310
DOI:
10.3892/or_00000357
[Indexed for MEDLINE]

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