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

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.
AuthorsCaryl J Antalis, Tyler Arnold, Tamkeen Rasool, Bonggi Lee, Kimberly K Buhman, Rafat A Siddiqui
JournalBreast cancer research and treatment (Breast Cancer Res Treat) Vol. 122 Issue 3 Pg. 661-70 (Aug 2010) ISSN: 1573-7217 [Electronic] Netherlands
PMID19851860 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cholesterol, LDL
  • RNA, Messenger
  • Receptors, Estrogen
  • ACAT1 protein, human
  • Acetyl-CoA C-Acetyltransferase
Topics
  • Acetyl-CoA C-Acetyltransferase (genetics, metabolism)
  • Blotting, Western
  • Breast Neoplasms (drug therapy, metabolism, pathology)
  • Cell Proliferation (drug effects)
  • Cholesterol, LDL (pharmacology)
  • Female
  • Humans
  • Neoplasms, Basal Cell (genetics, metabolism, pathology)
  • RNA, Messenger (genetics)
  • Receptors, Estrogen (metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured (drug effects)

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