Migration of MDA-MB-231 breast cancer cells depends on the availability of exogenous lipids and cholesterol esterification
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We previously described a lipid-accumulating phenotype of estrogen receptor negative (ER−) breast cancer cells exemplified by the MDA-MB-231 and MDA-MB-436 cell lines. These cells had more lipid droplets, a higher uptake of oleic acid and LDL, a higher ratio of cholesteryl ester (CE) to triacylglycerol (TAG), and higher expression of acyl-CoA:cholesterol acyltransferase 1 (ACAT1) as compared to ER+ MCF-7 breast cancer cells. LDL stimulated proliferation of ER-cells only, and proliferation was reduced by inhibition of ACAT. We hypothesized that storage of exogenous lipids would confer an energetic advantage. We tested this by depriving cells of exogenous lipids and measuring chemotactic migration, an energy-intensive behavior. MDA-MB-231 cells were grown for 48 h in medium with either 5% FBS or 5% lipoprotein-depleted (LD) FBS. Growth in LD medium resulted in visibly reduced lipid droplets and an 85% decrease in cell migration. Addition of LDL to the LD medium dose-dependently restored the ability to migrate in an ACAT-sensitive manner. LDL receptor (LDLR) mRNA was 12-fold higher in MDA-MB-231 cells compared to nontumorigenic ER-MCF-10A breast epithelial cells grown in LD medium. Addition of LDL to the LD medium reduced LDLR mRNA levels in MCF-10A cells only. We asked if ACAT1 activity was associated with the expression of the LDLR in MDA-MB-231 cells. LDLR mRNA in MDA-MB-231 cells was substantially reduced by inhibition of ACAT, demonstrating that high ACAT1 activity permitted higher LDLR expression. This data substantiates the association of lipid accumulation with aggressive behavior in an ER-breast cancer cell line.
KeywordsChemotactic migration Triple negative breast cancer Cholesterol esterification ACAT1 LDLR
The authors would like to thank Cary Mariash for helpful discussions and critique of the manuscript. We thank Pfizer, Inc., for providing the ACAT inhibitor CP-113818. This study was supported by a Clarian Values Fund for Research grant (to CJA) and the Methodist Research Institute.
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