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High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation

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Abstract

The specific role of dietary fat in breast cancer progression is unclear, although a low-fat diet was associated with decreased recurrence of estrogen receptor alpha negative (ER−) breast cancer. ER− basal-like MDA-MB-231 and MDA-MB-436 breast cancer cell lines contained a greater number of cytoplasmic lipid droplets compared to luminal ER+ MCF-7 cells. Therefore, we studied lipid storage functions in these cells. Both triacylglycerol and cholesteryl ester (CE) concentrations were higher in the ER− cells, but the ability to synthesize CE distinguished the two types of breast cancer cells. Higher baseline, oleic acid- and LDL-stimulated CE concentrations were found in ER− compared to ER+ cells. The differences corresponded to greater mRNA and protein levels of acyl-CoA:cholesterol acyltransferase 1 (ACAT1), higher ACAT activity, higher caveolin-1 protein levels, greater LDL uptake, and lower de novo cholesterol synthesis in ER− cells. Human LDL stimulated proliferation of ER− MDA-MB-231 cells, but had little effect on proliferation of ER+ MCF-7 cells. The functional significance of these findings was demonstrated by the observation that the ACAT inhibitor CP-113,818 reduced proliferation of breast cancer cells, and specifically reduced LDL-induced proliferation of ER− cells. Taken together, our studies show that a greater ability to take up, store and utilize exogenous cholesterol confers a proliferative advantage to basal-like ER− breast cancer cells. Differences in lipid uptake and storage capability may at least partially explain the differential effect of a low-fat diet on human breast cancer recurrence.

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Acknowledgments

The authors would like to thank Maureen Harrington and Cary Mariash for helpful discussions. Gene expression data from the public/private consortium, the Expression Project for Oncology, led by the International Genomics Consortium, were included in this study. We thank Pfizer, Inc., for providing the ACAT inhibitor CP-113,818. This study was supported by the Clarian Values Fund for Research.

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Authors and Affiliations

  1. Cellular Biochemistry Laboratory, Methodist Research Institute, 1800 N. Capitol Ave, E504, Indianapolis, IN, 46202, USA

    Caryl J. Antalis, Tamkeen Rasool & Rafat A. Siddiqui

  2. Department of Foods and Nutrition, Purdue University, West Lafayette, IN, 47907, USA

    Bonggi Lee & Kimberly K. Buhman

  3. Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Tyler Arnold & Rafat A. Siddiqui

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  1. Caryl J. Antalis
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  6. Rafat A. Siddiqui
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Correspondence to Caryl J. Antalis.

Additional information

ACAT1 is the commonly used name for acyl-CoA: cholesterol acyltransferase; the gene symbol is SOAT1.

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Antalis, C.J., Arnold, T., Rasool, T. et al. High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation. Breast Cancer Res Treat 122, 661–670 (2010). https://doi.org/10.1007/s10549-009-0594-8

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  • DOI: https://doi.org/10.1007/s10549-009-0594-8

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