Tamoxifen regulates cell fate through mitochondrial estrogen receptor beta in breast cancer

被引：0
作者：
M Razandi
A Pedram
V C Jordan
S Fuqua
E R Levin
机构：
[1] Medical Service (111-I),Division of Endocrinology
[2] Veterans Affairs Medical Center,Departments of Medicine and Biochemistry
[3] The University of California,undefined
[4] The Lombardi Cancer Center,undefined
[5] Georgetown University,undefined
[6] Baylor College of Medicine,undefined
来源：
Oncogene | 2013年 / 32卷
关键词：
estrogen receptor; mitochondria; apoptosis; tamoxifen resistance;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
Tamoxifen (TAM) has both cytostatic and cytotoxic properties for breast cancer. TAM engaged mitochondrial estrogen receptor beta (ERβ) as an antagonist in MCF7-BK cells, increasing reactive oxygen species (ROS) concentrations from the mitochondria that were required for cytotoxicity. In part, this derived from TAM downregulating manganese superoxide dismutase (MnSOD) activity by causing the nitrosylation of tyrosine 34, thereby increasing ROS. ROS-activated protein kinase C delta and c-jun N-terminal kinases, resulting in the mitochondrial translocation of Bax and cytochrome C release. Interestingly, TAM failed to cause high ROS levels or induce cell death in MCF7-BK-TR cells due to stimulation of MnSOD activity through agonistic effects at mitochondrial ERβ. In several mouse xenograft models, lentiviral shRNA-induced knockdown of MnSOD caused tumors that grew in the presence of TAM to undergo substantial apoptosis. Tumor MnSOD and mitochondrial ERβ are therefore targets for therapeutic intervention to reverse TAM resistance and enhance a cell death response.
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页码：3274 / 3285
页数：11
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