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

Oncol Rep. 2009 May;21(5):1317-22. doi: 10.3892/or_00000357.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Breast / drug effects
  • Breast / pathology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / pathology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Epithelial Cells / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, ras
  • Humans
  • Lovastatin / pharmacology*
  • Matrix Metalloproteinase 2 / biosynthesis
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Signal Transduction
  • Simvastatin / pharmacology*
  • ras Proteins / biosynthesis
  • ras Proteins / genetics


  • Antineoplastic Agents
  • Lovastatin
  • Simvastatin
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • ras Proteins