Atorvastatin Improves Cisplatin Sensitivity Through Modulation of Cholesteryl Ester Homeostasis in Breast Cancer Cells

Abstract Background: Acquired treatment resistance is a major problem in breast cancer management. Alterations in lipid metabolism have been proposed to contribute to tumor progression and the development of drug resistance. The present study aimed to identify the role of cholesteryl ester (CE) metabolism in MCF-7 and MDA-MB-231 breast cancer cell line response to cisplatin (CDDP) treatment in the acute setting. Methods: MCF-7 (luminal A), MDA-MB-231 (triple-negative) and CDDP-resistant MDA-MB-231 (MDACR) cell lines were grown in the presence or absence of CDDP in combination with atorvastatin (ATV), lipid depletion or low-density lipoprotein (LDL) loading and were analyzed by a variety of biochemical and radiometric techniques. Results: Co-administration of CDDP and ATV strongly reduced cell proliferation and viability to a greater extent than CDDP alone, especially in MDA-MB-231 cells. These findings were associated with reduced CE synthesis and storage in MDA-MB-231 cells. In MDACR cells, acetyl-CoA acetyltransferase 1 (ACAT-1) was upregulated compared to naïve MDA-MB-231 cells and ATV treatment restored CDDP sensitivity, suggesting that aberrant ACAT-1 expression contributes to CDDP resistance in TNBC cells. Conclusions: These findings indicate that the elevated susceptibility of MDA-MB-231 cells to co-administration of CDDP and ATV, is associated with an increased reliance on CE availability. Our data from these cell culture-based studies supports the upregulation of cholesterol homeostasis as an adaptive response that contributes to aggressiveness and chemotherapy resistance.