Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo
Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo
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DOI：
10.1093/jnci/92.23.1926
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发表时间：
2000-12-06
期刊：
影响因子：
--
通讯作者：
Osborne, CK
中科院分区：
文献类型：
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作者：
Schiff, R;Reddy, P;Osborne, CK
背景：大多数乳腺癌，即使最初对他莫昔芬有反应，最终也会产生耐药性。这种耐药性的分子基础尚不清楚，在一些患者中，这种耐药性被认为与他莫昔芬刺激肿瘤生长有关。他莫昔芬诱导细胞氧化应激，因为细胞氧化还原状态的变化可以激活信号通路，导致激活蛋白-1（AP-1）的激活，我们研究了他莫昔芬耐药生长在体内是否与氧化应激和/或AP-1在异种移植模型系统中的激活有关，其中耐药是由他莫昔芬刺激的生长引起的。研究方法：通过测量抗氧化酶（例如，超氧化物歧化酶[SOD]、谷胱甘肽S-转移酶[GST]和磷酸己糖分流[HMS]）活性、谷胱甘肽和脂质过氧化。通过蛋白质印迹分析检测AP-1蛋白水平、磷酸化c-jun水平和磷酸化Jun NH 2-末端激酶（JNK）水平，并通过电泳迁移率变动测定和报告基因系统评估AP-1 DNA结合和转录活性。所有统计检验均为双侧检验。结果如下：与对照雌激素治疗的肿瘤相比，他莫昔芬耐药肿瘤的SOD（超过3倍; P = 0.004）和GST（2倍; P = 0.004）活性在统计学上显著增加，谷胱甘肽水平在统计学上显著降低（超过2倍; P
Background: Most breast cancers, even those that are initially responsive to tamoxifen, ultimately become resistant. The molecular basis for this resistance, which in some patients is thought to involve stimulation of tumor growth by tamoxifen, is unclear. Tamoxifen induces cellular oxidative stress, and because changes in cell redox state can activate signaling pathways leading to the activation of activating protein-1 (AP-1), we investigated whether tamoxifen-resistant growth in vivo is associated with oxidative stress and/or activation of AP-I in a xenograft model system where resistance is caused by tamoxifen-stimulated growth. Methods: Control estrogen-treated, tamoxifen-sensitive, and tamoxifen-resistant MCF-7 xenograft tumors were assessed for oxidative stress by measuring levels of antioxidant enzyme (e.g., superoxide dismutase [SOD], glutathione S-transferase [GST], and hexose monophosphate shunt [HMS]) activity, glutathione, and lipid peroxidation. AP-1 protein levels, phosphorylated c-jun levels, and phosphorylated Jun NH2-terminal kinase (JNK) levels were examined by western blot analyses, and AP-l DNA-binding and transcriptional activities were assessed by electrophoretic mobility shift assays and a reporter gene system. All statistical tests are two-sided. Results: Compared with control estrogen-treated tumors, tamoxifen resistant tumors had statistically significantly increased SOD (more than threefold; P = .004) and GST (twofold; P = .004) activity and statistically significantly reduced glutathione levels (greater than twofold; P