Breast cancer inhibition by statins

Abstract

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 hydrophobic statins have direct anticancer activity. There is a >2 log IC50 range in statin sensitivity (e.g. IC50 for S and F: <1um in MDA-231 vs. 91 and 85 for MCF-7, respectively). Cells with activated Ras or ErbB2 pathways appeared more sensitive than those overexpressing ER or cyclin D1. The NCI/DTP screen of L and S against >50 non-breast human cancer cell lines produced mean cytotoxic values (LC50, 48h) of 29 uM and 25 uM, respectively; with no apparent correlation between L and S on these cell lines (COMPARE analysis). Only S and F produced promoter-specific oncogene inhibition, with ErbB2 showing greater promoter sensitivity than cyclinD1. Finally, oral dosing of S (1–2mg/kg/day) in mice implanted with MCNeuA mammary cancer cells produced 50% inhibition in mean tumor size by day 27 (518 vs. 1019 mm3; p<0.001). Conclusions: Hydrophobic statins exert direct anticancer activity in vitro, especially in cell lines with activated Ras or ErbB2 pathways, and inhibit ErbB2-dependent breast tumorigenic growth in vivo at a daily dose comparable to that approved for cholesterol reduction in humans. Among the statins tested, F demonstrated the most potent antiproliferative and oncogene-specific inhibitory activity. No significant financial relationships to disclose.