Simvastatin Downregulates HER2 via Upregulation of PEA3 to Induce Cell Death in HER2-Positive Breast Cancer Cells

Simvastatin is a widely used cholesterol-adjusting drug that selectively inhibits the 3-hyrdoxy-3-methylglutaryl-coenzyme A reductase, leading to decreased cholesterol biosynthesis. Notably, through this activity, simvastatin exerts antiproliferative and proapoptotic effects on various cancer cells, including non-small cell lung and breast cancer. Although statin-induced breast cancer cell death is nitric oxide inducible and arginase dependent, we report alternative mechanisms relative to the antitumor function of simvastatin in breast cancer cells. Simvastatin induced cell death in MDA-MB-361, SK-Ov3, and SKBR3, HER2-overexpressing cell lines, in both time- and dose-dependent manners, but did not exert cytotoxicity in MCF10A and MDA-MB-231, HER2 low/negative cell lines. The protein expression of HER2 decreased after the cells were treated with simvastatin; however, HER2 protein and mRNA stabilities were not changed. Furthermore, simvastatin inhibited the activity of the HER2 promoter. Simvastatin-induced cytotoxicity and promoter activity repression were reversed by mevalonate and GGPP, the immediate metabolic products of the acetyl CoA/3-hyrdoxy-3-methylglutaryl CoA reductase reaction and the isoprenoid of the mevalonate cascade, respectively. In addition, simvastatin treatment induced the expression of PEA3, which is a HER2 promoter inhibitor. The use of siRNA to downregulate expression of PEA3 inhibited the simvastin-induced HER2 repression and cell death. These findings provide alternative mechanisms for the antitumor effects of simvastatin, suggesting that simvastatin could also be used as a combination therapy with other chemotherapy agents in HER2-positive patients.