High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation
High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation
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DOI：
10.1007/s10549-009-0594-8
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发表时间：
2010-08-01
影响因子：
3.8
通讯作者：
Siddiqui, Rafat A.
中科院分区：
文献类型：
--
作者：
Antalis, Caryl J.;Arnold, Tyler;Siddiqui, Rafat A.
膳食脂肪在乳腺癌进展中的具体作用尚不清楚，尽管低脂饮食与雌激素受体α阴性（ER-）乳腺癌复发率降低相关。与管腔ER+ MCF-7细胞相比，ER-基底样MDA-MB-231和MDA-MB-436乳腺癌细胞系含有更多数量的细胞质脂滴。因此，我们研究了这些细胞中的脂质储存功能。三酰甘油和胆固醇酯（CE）的浓度较高的ER-细胞，但合成CE的能力区分两种类型的乳腺癌细胞。与ER+细胞相比，ER-细胞的基线、油酸和LDL刺激CE浓度更高。这些差异对应于ER-细胞中酰基辅酶A：胆固醇酰基转移酶1（ACAT 1）的mRNA和蛋白质水平更高、ACAT活性更高、小窝蛋白-1蛋白质水平更高、LDL摄取更高和胆固醇从头合成更低。人LDL刺激ER-MDA-MB-231细胞增殖，但对ER+ MCF-7细胞增殖影响不大。通过观察到ACAT抑制剂CP-113，818减少乳腺癌细胞的增殖，并且特别减少LDL诱导的ER-细胞的增殖，证明了这些发现的功能意义。总之，我们的研究表明，更大的吸收、储存和利用外源性胆固醇的能力赋予基底样ER-乳腺癌细胞增殖优势。脂质摄取和储存能力的差异至少可以部分解释低脂饮食对人类乳腺癌复发的差异效应。
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.