Avasimibe Abolishes the Efficacy of Fluvastatin for the Prevention of Cancer in a Spontaneous Mouse Model of Breast Cancer

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 (<i>ACAT</i>)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 <i>ACAT2</i> 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.