Can Statin Therapy Reduce the Risk of Breast Cancer

The statins are a class of cholesterol-lowering drugs first marketed in 1987. They are commonly used among persons aged 50 years and older, and atorvastatin is among the 10 most commonly prescribed drugs in the United States. A growing body of laboratory data suggests that the statins may have chemopreventive potential against cancer at various sites, including colon, lung, breast, and prostate. The statins inhibit the synthesis of cholesterol by inhibiting a key enzyme in the cholesterol pathway, 3-hydroxy3-methylglutaryl– coenzyme A (HMG-CoA) reductase. The growth-suppressing properties of the statins may be a result of the inhibition of HMG-CoA reductase, but other mechanisms have also been suggested. Lovastatin and simvastatin suppress the growth of cancer cells in vitro by causing the cells to pause in the G1 phase of the mitotic cycle and by increasing cell death (apoptosis). Statins prevent the conversion of HMG-CoA into mevalonic acid. When mevalonate levels decrease with statin therapy, isoprenylation of key signal transduction proteins (such as Ras, Rap, and others) is prevented, their subcellular localization is disrupted, and they are inactivated as signal transducers. Administration of lovastatin to cells in culture impacts cell cycle progression. Lovastatin effectively synchronizes both tumor and normal cells and arrests cells in G1. The cell cycle pathways perturbed by lovastatin result in the induction of cyclin-dependent kinase inhibitors (CKIs) p21 and/or p27 independent of other standard G1-arresting agents or conditions such as serum starvation or double thymidine block. Additionally, the lovastatin-mediated G1 arrest and p21/ p27 induction occur independently of the ras signaling pathway/function. Stabilization of p21 and p27 may be the result of a previously unknown function of the prodrug, beta-lactone ring form of lovastatin to inhibit the proteasome degradation of these CKIs. Mevalonate (which rescues cells from statin arrest) unexpectedly abrogates the lovastatin prodrug inhibition of the proteasome. Mevalonate increases the activity of the proteasome, which results in degradation of the CKIs, allowing lovastatin-arrested cells to resume cell division. The lovastatin-mediated inhibition of the proteasome suggests a unique mechanism for the putative chemopreventive effects of statins in human cancer. Two statins (atorvastatin and fluvastatin) are able to inhibit the proliferation of MCF-7 breast cancer cells in the absence of estradiol. This effect seems to depend on an apoptotic statin effect that may be mediated by the downregulation of the antiapoptotic protein Bcl-2, rather than upregulation of Fas-L or p53. However, in the presence of estradiol, the inhibitory effect of the statins is less pronounced. These mechanisms suggest that statins may have the ability to reduce the development of several human malignancies. Individual, mostly retrospective studies have found sometimes large reductions in the risk of breast cancer associated with the use of statin therapy. A recent study reported by Kochhar et al investigated the effect of statins on the development of breast cancer in a US female veterans population. Patients were considered to be statin users if they were taking statins before a diagnosis of breast cancer. However, dose, duration, and type of statin used were not factored into the analysis. Multiple logistic regression analysis was used to calculate the odds ratios (OR) and 95% CIs, and the data were adjusted for age, smoking, alcohol use, and diabetes. A total of 40,421 women were studied, and statin users were less likely to have developed breast cancer (OR 0.49; 95% CI, 0.38 to 0.62; P .0001) than women who were not statin users. Therefore, statin use was associated with a 51% risk reduction of breast cancer after controlling for age, smoking, alcohol use, and diabetes. Conversely, Newman and Hulley reviewed the findings on rodent carcinogenicity of lipid-lowering drugs and concluded that fibrates and HMG-CoA reductase inhibitors initiate or promote cancer in rodents. In some cases, the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 34 DECEMBER 1 2005