1003 Background: Statins are potent cholesterol-lowering drugs with pleiotropic activities including inhibition of Ras, Rac and Rho isoprenylation, altered PI3K/AKT activity and eNOS production, and reduced ubiquinone synthesis. These activities are independent of cholesterol reduction and may explain the prevention of breast cancer and other malignancies seen in a number of studies. Methods: We compared hydrophilic (pravastatin, P) vs. hydrophobic (lovastatin, L; simvastatin, S; fluvastatin, F) statins for their in vitro growth inhibitory effects on a panel of human breast cancer cell lines: MDA-MB-231, SKBR3, BT-474, and MCF-7. To evaluate statin potential to silence expression of specific oncogenes, stable MCF-7 sublines expressing ErbB2 or cyclinD1 promoter-driven luciferase reporters were assayed for growth and promoter activity after statin treatment. Finally, we evaluated the in vivo impact of statin administration in a murine ErbB2 breast cancer model. Results: In vitro results indicate that only ...