Increased STAT1 signaling in endocrine-resistant breast cancer.
Increased STAT1 signaling in endocrine-resistant breast cancer.
复制标题
DOI：
10.1371/journal.pone.0094226
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Langdon SP
中科院分区：
文献类型：
--
作者：
Huang R;Faratian D;Sims AH;Wilson D;Thomas JS;Harrison DJ;Langdon SP
对雌激素/他莫昔芬敏感的MCF-7细胞系及其部分敏感（MCF-7/LCC1）和完全耐药（MCF-7/LCC9）变异进行蛋白质组学分析，以确定乳腺癌内分泌敏感性的修饰因子。通过对肿瘤发生和肿瘤抑制通路中120对磷酸化和非磷酸化表位的表达分析发现，STAT1和几个磷酸化表位（phospho-STAT1（Tyr701）和phospho-STAT3(Ser727)）在内分泌抗性和亲本对照中存在差异表达，qRT-PCR和western blotting证实了这一点。STAT1抑制剂EGCG对内分泌耐药的MCF-7/LCC1和MCF-7/LCC9细胞比亲代MCF-7细胞更有效，而STAT3抑制剂Stattic和WP1066对内分泌耐药和亲代MCF-7细胞同样有效。当与他莫昔芬联合在体外试验时，STAT抑制剂的作用是相加的，而不是协同的。采用定量免疫荧光法检测侵袭性乳腺癌及配对淋巴结中STAT1和STAT3的表达。当将淋巴结表达与其配对的原发性乳腺癌表达进行比较时，淋巴结中细胞质STAT1（~ 3.1倍）、磷酸化stat3 (Ser727)（~ 1.8倍）、STAT5（~ 1.5倍）和细胞核磷酸化stat3 (Ser727)（~ 1.5倍）的表达更高。从公开的基因表达数据集（GSE2990, GSE12093, GSE6532）分析了550例乳腺癌中STAT1和STAT3转录物的表达水平。当考虑使用他莫昔芬治疗时，STAT1基因表达几乎可以预测远处无转移生存（DMFS, log-rank p = 0.067），而STAT3基因表达可以预测DMFS （log-rank p<0.0001）。对546例乳腺癌中STAT1和STAT3蛋白表达的分析也表明，STAT3蛋白的高表达与生存率的提高相关（DMFS, p = 0.006）。这些结果表明STAT信号在内分泌抵抗中是重要的，并且STAT抑制剂可能代表乳腺癌的潜在治疗方法，甚至在抵抗环境中。
Proteomic profiling of the estrogen/tamoxifen-sensitive MCF-7 cell line and its partially sensitive (MCF-7/LCC1) and fully resistant (MCF-7/LCC9) variants was performed to identify modifiers of endocrine sensitivity in breast cancer. Analysis of the expression of 120 paired phosphorylated and non-phosphorylated epitopes in key oncogenic and tumor suppressor pathways revealed that STAT1 and several phosphorylated epitopes (phospho-STAT1(Tyr701) and phospho-STAT3(Ser727)) were differentially expressed between endocrine resistant and parental controls, confirmed by qRT-PCR and western blotting. The STAT1 inhibitor EGCG was a more effective inhibitor of the endocrine resistant MCF-7/LCC1 and MCF-7/LCC9 lines than parental MCF-7 cells, while STAT3 inhibitors Stattic and WP1066 were equally effective in endocrine-resistant and parental lines. The effects of the STAT inhibitors were additive, rather than synergistic, when tested in combination with tamoxifen in vitro. Expression of STAT1 and STAT3 were measured by quantitative immunofluorescence in invasive breast cancers and matched lymph nodes. When lymph node expression was compared to its paired primary breast cancer expression, there was greater expression of cytoplasmic STAT1 (∼3.1 fold), phospho-STAT3(Ser727) (∼1.8 fold), and STAT5 (∼1.5 fold) and nuclear phospho-STAT3(Ser727) (∼1.5 fold) in the nodes. Expression levels of STAT1 and STAT3 transcript were analysed in 550 breast cancers from publicly available gene expression datasets (GSE2990, GSE12093, GSE6532). When treatment with tamoxifen was considered, STAT1 gene expression was nearly predictive of distant metastasis-free survival (DMFS, log-rank p = 0.067), while STAT3 gene expression was predictive of DMFS (log-rank p<0.0001). Analysis of STAT1 and STAT3 protein expression in a series of 546 breast cancers also indicated that high expression of STAT3 protein was associated with improved survival (DMFS, p = 0.006). These results suggest that STAT signaling is important in endocrine resistance, and that STAT inhibitors may represent potential therapies in breast cancer, even in the resistant setting.
登录
查看更多内容
影响因子：
15.9
作者：
Bromberg, J
通讯作者：
Bromberg, J
影响因子：
6.4
作者：
Magkou, Christina;Giannopoulou, Ioanna;Nakopoulou, Lydia
通讯作者：
Nakopoulou, Lydia
影响因子：
11.5
作者：
Diaz, N;Minton, S;Muro-Cacho, CA
通讯作者：
Muro-Cacho, CA
影响因子：
6.4
作者：
Charpin, Colette;Secq, Veronique;Garcia, Stephane
通讯作者：
Garcia, Stephane
影响因子：
6
作者：
Dien, Jennifer;Amin, Hesham M.;Lai, Raymond
通讯作者：
Lai, Raymond