Abstract
The cholesterol biosynthesis pathway is upregulated during breast cancer development and progression. Inhibition of the aberrantly upregulated cholesterol pathway by statins reduces breast tumor incidence and burden by 50% in SV40 C3(1) TAg mice, a mouse model of triple negative breast cancer. We hypothesized that fluvastatin's preventive efficacy could be further enhanced by co-targeting the statin-induced restorative feedback pathways that tightly control the cholesterol pathway and are involved in resistance to statins. Acyl-coenzyme A: cholesterol acyltransferase (ACAT)2 is a cholesterol esterification gene that is upregulated in statin-resistant MCF10.DCIS cells, and in mammary tumors of statin-non-responsive SV40 C3(1) TAg mice. In support of this hypothesis, a combination of fluvastatin and avasimibe effectively inhibited the cell growth of statin-resistant MCF10.DCIS cells. However, this combination failed to prevent breast tumor formation in SV40 C3(1) TAg mice. Although avasimibe inhibited fluvastatin-induced ACAT2 mRNA expression in the breast tissue of the combination-treated mice, confirming that avasimibe effectively hit its target, the fluvastatin and avasimibe combination was completely ineffective in preventing breast cancer in vivo, with approximately 90% of mice developing tumors by 22 weeks, similar to the vehicle control group animals. These findings, along with avasimibe' s known interactions with CYP450 gene family members, suggest that AVA abrogates the efficacy of fluvastatin through enhanced metabolism of fluvastatin in vivo. The findings reported in this brief communication provide a cautionary note for studies proposing the use of avasimibe in combination therapy for cancer prevention and treatment.