ARTEMIN synergizes with TWIST1 to promote metastasis and poor survival outcome in patients with ER negative mammary carcinoma.
ARTEMIN synergizes with TWIST1 to promote metastasis and poor survival outcome in patients with ER negative mammary carcinoma.
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ARTEMIN 与 TWIST1 协同作用促进 ER 阴性乳腺癌患者的转移和不良生存结果
DOI：
10.1186/bcr3054
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Lobie PE
中科院分区：
文献类型：
--
作者：
Banerjee A;Wu ZS;Qian P;Kang J;Pandey V;Liu DX;Zhu T;Lobie PE
ARTEMIN（ARTN）是一种受雌激素调节的生长因子，其表达促进对抗雌激素疗法的耐药性，并预示着接受他莫昔芬治疗的雌激素受体（ER）阳性乳腺癌（ER + MC）患者的生存结果更差。ARTN也在ER阴性乳腺癌（ER - MC）中表达。在此，我们确定了ARTN在ER - MC中的作用，并明确了导致患者预后不良的作用机制。
我们通过强制表达或小干扰RNA（siRNA）介导的耗竭来调节两种ER -（间充质/低紧密连接蛋白）乳腺癌细胞系（BT549和MDA - MB - 231）中ARTN的表达。通过各种体外致癌性检测方法，包括TWIST1信使RNA（mRNA）和蛋白质的表达，来检测ARTN表达调节的影响。体外结果与免疫缺陷小鼠的异种移植研究相关联。在一组ER - MC患者中检测了ARTN和TWIST1的共表达以及它们与不良生存结果的关联。通过对AKT磷酸化（pAKT - Ser 473）的药理抑制或TWIST1表达的调节进行通路分析。
ARTN表达使ER - MC细胞具有增强的间充质特性，包括侵袭性增加以及与增强的间充质表型一致的基因表达谱。ARTN刺激ER - MC细胞的非贴壁生长和3D基质胶生长、内皮细胞黏附以及ER - MC细胞穿过内皮细胞屏障的迁移。ARTN的强制表达产生更大的、局部侵袭性的肿瘤肿块，伴有肿瘤栓子，可发生远处转移。ARTN调节ER - MC细胞中TWIST1的表达，并且在一组乳腺癌细胞系以及一组ER - MC患者中，ARTN表达与TWIST1表达显著相关。ARTN和TWIST1两者低表达预示着ER - MC患者100%无复发且总体生存良好，而两者高表达则与不良生存结果相关。ARTN通过增加AKT活性刺激TWIST1表达增加。siRNA介导的TWIST1耗竭消除了ARTN刺激的与转移相关的细胞行为，而TWIST1的强制表达消除了ARTN耗竭的功能效应。
ARTN和TWIST1协同作用使ER - MC患者预后更差，因此联合抑制ARTN和磷脂酰肌醇3 - 激酶/蛋白激酶B（PI3K/AKT）可能为这种乳腺癌亚型提供一种新的治疗策略。
IntroductionARTEMIN (ARTN) is an estrogen regulated growth factor, the expression of which promotes resistance to antiestrogen therapies and predicts poorer survival outcome of patients with estrogen receptor (ER) positive mammary carcinoma (ER+MC) treated with tamoxifen. ARTN is also expressed in ER negative mammary carcinoma (ER-MC). Herein, we determined the role of ARTN in ER-MC and defined the mechanism of action producing poor patient prognosis.MethodsWe modulated the expression of ARTN in two ER- (mesenchymal/claudin-low) mammary carcinoma cell lines (BT549 and MDA-MB-231) by forced expression or small interfering RNA (siRNA) mediated depletion. The effects of modulation of ARTN expression were examined by variousin vitromeasures of oncogenicity, including the expression of TWIST1 messenger RNA (mRNA) and protein.In vitroresults were correlated to xenograft studies in immunodeficient mice. Co-expression of ARTN and TWIST1 and their association to poor survival outcome were examined in a cohort of patients with ER-MC. Pathway analysis was performed by pharmacological inhibition of phosphorylation of AKT (pAKT-Ser 473) or modulation of TWIST1 expression.ResultsARTN expression resulted in ER-MC cells with enhanced mesenchymal characteristics, including increased invasion and a gene expression profile consistent with enhanced mesenchymal phenotype. ARTN stimulated ER-MC cell anchorage independent and 3D matrigel growth, endothelial cell adhesion and transmigration of ER-MC cells through an endothelial cell barrier. Forced expression of ARTN produced a larger, locally invasive tumour mass with tumour emboli that produced distant metastasis. ARTN regulated TWIST1 expression in ER-MC cells and ARTN expression was significantly correlated to TWIST1 expression in a panel of mammary carcinoma cell lines and in a cohort of patients with ER-MC. Low expression of both ARTN and TWIST1 predicted 100% relapse free and overall survival in patients with ER-MC, whereas high expression of both ARTN and TWIST1 was associated with a poor survival outcome. ARTN stimulated an increase in TWIST1 expression via increased AKT activity. siRNA mediated depletion of TWIST1 abrogated ARTN stimulated cellular behaviour associated with metastasis, and forced expression of TWIST1 abrogated the functional effects of ARTN depletion.ConclusionsARTN and TWIST1 synergize to produce a worse outcome in ER-MC and combined inhibition of ARTN and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) may therefore provide a novel therapeutic strategy in this subtype of mammary carcinoma.
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影响因子：
8
作者：
Miyagawa, S;Katsu, Y;Iguchi, T
通讯作者：
Iguchi, T
Twist1介导的阿霉素诱导的上皮-间质转化与乳腺癌细胞的多药耐药性和侵袭潜力相关
影响因子：
11.5
作者：
Li, Qing-Quan;Xu, Jing-Da;Xu, Zu-De
通讯作者：
Xu, Zu-De
影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
影响因子：
50.3
作者：
Ansieau, Stephane;Bastid, Jeremy;Puisieux, Alain
通讯作者：
Puisieux, Alain
DOI：
10.1016/s0360-3016(99)00158-3
发表时间：
1999-08-01
影响因子：
7
作者：
Elkhuizen, PHM;Voogd, AC;van de Vijver, MJ
通讯作者：
van de Vijver, MJ