Improving the efficacy of hormone therapy in breast cancer: The role of cholesterol metabolism in SERM-mediated autophagy, cell differentiation and death
Improving the efficacy of hormone therapy in breast cancer: The role of cholesterol metabolism in SERM-mediated autophagy, cell differentiation and death
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DOI：
10.1016/j.bcp.2017.06.120
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发表时间：
2017-11-15
影响因子：
5.8
通讯作者：
Silvente-Poirot, Sandrine
中科院分区：
文献类型：
--
作者：
Leignadier, Julie;Dalenc, Florence;Silvente-Poirot, Sandrine
乳腺癌是世界上最常见的女性癌症之一，雌激素受体（ER）阳性乳腺癌是最常见的亚型。他莫昔芬（Tamoxifen，Tam）是一种竞争性结合ER的有效药物，通常用于治疗ER阳性BC。然而，许多ER阳性BC对Tam治疗没有反应，并且经常观察到获得性耐药性，这对延长患者预期寿命构成了重大挑战。导致这些治疗失败的机制尚不清楚，这表明需要其他靶点和更好的预测患者对Tam的反应。Tam感兴趣的脱靶点之一是微粒体抗雌激素结合位点（AEBS），一种由胆固醇-5，6-环氧化物水解酶（ChEH）组成的多蛋白复合物，参与胆固醇生物合成的后期阶段。Tam和其他选择性ER调节剂在药理学剂量下刺激氧化应激并抑制ChEH亚基，触发负责BC细胞分化和死亡的胆固醇-5，6-环氧化物代谢物的产生和积累。然而，AEBS亚基的胆固醇生成活性的抑制也诱导固醇前体的积累，其触发存活自噬以损害Tam的功效。总而言之，这些研究强调了胆固醇代谢在Tam药理学中的参与，为如何提高其在BC和其他癌症中的治疗效果提供了新的线索，并为开发更有效的BC治疗药物提供了新的理论基础。(C)2017爱思唯尔公司All rights reserved.
Breast cancer (BC) is one of the most common female cancers in the world, with estrogen receptor (ER) positive BC the most frequent subtype. Tamoxifen (Tam) is an effective drug that competitively binds to the ER and is routinely used for the treatment of ER-positive BC. However, a number of ER-positive BC do not respond to Tam treatment and acquired resistance is often observed, constituting a major challenge for extending patient life expectancy. The mechanisms responsible for these treatment failures remain unclear, indicating the requirement for other targets and better predictors for patient response to Tam. One of Tam's off-targets of interest is the microsomal antiestrogen binding site (AEBS), a multiproteic complex made up of the cholesterol-5,6-epoxide hydrolase (ChEH) enzymes that are involved in the late stages of cholesterol biosynthesis. Tam and other selective ER modulators stimulate oxidative stress and inhibit the ChEH subunits at pharmacological doses, triggering the production and accumulation of cholesterol-5,6-epoxide metabolites responsible for BC cell differentiation and death. However, inhibition of the cholesterogenic activity of the AEBS subunits also induces the accumulation of sterol precursors, which triggers a survival autophagy to impair Tam's efficacy. Altogether, these studies have highlighted the involvement of cholesterol metabolism in the pharmacology of Tam that has provided new clues on how to improve its therapeutic efficacy in both BC and other cancers as well as offering a new rationale for developing more efficient drugs for BC treatment. (C) 2017 Elsevier Inc. All rights reserved.