Obesity, cholesterol metabolism, and breast cancer pathogenesis.
Obesity, cholesterol metabolism, and breast cancer pathogenesis.
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DOI：
10.1158/0008-5472.can-14-1756
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发表时间：
2014-09-15
期刊：
影响因子：
11.2
通讯作者：
Nelson ER
中科院分区：
文献类型：
--
作者：
McDonnell DP;Park S;Goulet MT;Jasper J;Wardell SE;Chang CY;Norris JD;Guyton JR;Nelson ER
肥胖和脂质代谢改变是绝经前和绝经后女性患乳腺癌的危险因素。这些病理关系部分归因于胆固醇对细胞膜生物物理特性的影响以及这些变化对细胞膜引发的信号事件的影响。然而，最近的研究表明，氧甾醇 27-羟基胆固醇 (27HC)，而不是胆固醇本身，可能是脂质代谢与癌症之间的主要生化联系。负责从胆固醇生成 27HC 的酶 CYP27A1 主要在肝脏和巨噬细胞中表达。此外，还观察到这种酶在乳腺肿瘤内的表达显着升高。据信，27HC 通过巨噬细胞和可能的其他细胞中的肝脏 X 受体 (LXR) 发挥作用，参与维持机体胆固醇稳态。最近还表明，27HC 是乳腺癌细胞中的雌激素受体 (ER) 激动剂，并且它可以刺激多种乳腺癌模型中的肿瘤生长和转移。这些发现为干扰胆固醇/27HC 合成的药物方法的临床评估提供了理论基础，作为减轻胆固醇对乳腺癌发病机制影响的手段。
Obesity and altered lipid metabolism are risk factors for breast cancer in pre- and post-menopausal women. These pathologic relationships have been attributed in part to the impact of cholesterol on the biophysical properties of cell membranes and to the influence of these changes on signaling events initiated at the membrane. However, more recent studies have indicated that the oxysterol 27-hydroxycholesterol (27HC), and not cholesterol per se, may be the primary biochemical link between lipid metabolism and cancer. The enzyme responsible for production of 27HC from cholesterol, CYP27A1, is expressed primarily in the liver and in macrophages. In addition significantly elevated expression of this enzyme within breast tumors has also been observed. It is believed that 27HC, acting through the liver X receptor (LXR) in macrophages and possibly other cells is involved in maintaining organismal cholesterol homeostasis. It has also been shown recently that 27HC is an estrogen receptor (ER) agonist in breast cancer cells and that it stimulates the growth and metastasis of tumors in several models of breast cancer. These findings provide the rationale for the clinical evaluation of pharmaceutical approaches that interfere with cholesterol/27HC synthesis as a means to mitigate the impact of cholesterol on breast cancer pathogenesis.