Co-expression of HER2 and HER3 receptor tyrosine kinases enhances invasion of breast cells via stimulation of interleukin-8 autocrine secretion.
Co-expression of HER2 and HER3 receptor tyrosine kinases enhances invasion of breast cells via stimulation of interleukin-8 autocrine secretion.
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DOI：
10.1186/bcr3329
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发表时间：
2012-10-12
期刊：
影响因子：
--
通讯作者：
Bentires-Alj M
中科院分区：
文献类型：
--
作者：
Aceto N;Duss S;MacDonald G;Meyer DS;Roloff TC;Hynes NE;Bentires-Alj M
酪氨酸激酶受体HER 2和HER 3在乳腺癌中起重要作用。HER 2/HER 3异源二聚体是一个关键的致癌单位，与减少无复发和降低总生存期相关。虽然已经在翻译后修饰水平上广泛研究了HER 2和HER 3下游的信号级联，但关于HER 2/HER 3过表达和激活对乳腺癌基因表达的影响知之甚少。我们现在已经确定了乳腺细胞中HER 2/HER 3单位激活诱导的遗传景观，并确定了白细胞介素（IL）8和CXCR 1作为治疗HER 2/HER 3过度表达乳腺癌的潜在治疗靶点。使用三维（3D）培养、侵袭和迁移测定来确定HER 2和HER 3共表达和活化的作用。进行基因表达分析以鉴定3D培养物中由HER 2/HER 3诱导的基因网络。使用生物信息学分析和中和抗体来鉴定HER 2/HER 3诱发的侵袭的关键介质。酪氨酸激酶受体HER 2和HER 3的共表达诱导MCF 10A细胞的迁移和侵袭。这些细胞的微阵列分析揭示了包含80种上调转录物的特异性“HER 2/HER 3特征”，其中IL 8是最高的（11倍上调）。值得注意的是，对公共数据集的检查显示，在HER 2富集的原发性乳腺肿瘤和基底样原发性乳腺肿瘤中，IL 8转录物水平较高，这两种亚型的特征是预后特别差。此外，IL 8表达与高肿瘤分级和ER阴性状态相关。重要的是，用IL 8中和抗体处理阻止了3D培养物中MCF 10A-HER 2/HER 3和BT474细胞的侵袭，突出了IL 8自分泌信号传导在HER 2/HER 3活化后的重要性。我们的研究结果表明，HER 2和HER 3共表达诱导IL 8自分泌信号，导致乳腺细胞的侵袭。靶向IL 8或其受体CXCR 1的药物可用于治疗具有侵袭性特征的HER 2/HER 3/IL 8阳性乳腺癌。
The tyrosine kinase receptors HER2 and HER3 play an important role in breast cancer. The HER2/HER3 heterodimer is a critical oncogenic unit associated with reduced relapse-free and decreased overall survival. While signaling cascades downstream of HER2 and HER3 have been studied extensively at the level of post-translational modification, little is known about the effects of HER2/HER3 overexpression and activation on gene expression in breast cancer. We have now defined the genetic landscape induced by activation of the HER2/HER3 unit in mammary cells, and have identified interleukin (IL)8 and CXCR1 as potential therapeutic targets for the treatment of HER2/HER3-overexpressing breast cancers. Three-dimensional (3D) cultures, invasion and migration assays were used to determine the effects of HER2 and HER3 co-expression and activation. Gene expression analysis was performed to identify the gene network induced by HER2/HER3 in 3D cultures. Bioinformatic analysis and neutralizing antibodies were used to identify key mediators of HER2/HER3-evoked invasion. Co-expression of the tyrosine kinase receptors HER2 and HER3 induced migration and invasion of MCF10A cells. Microarray analysis of these cells revealed a specific "HER2/HER3 signature" comprising 80 upregulated transcripts, with IL8 being the highest (11-fold upregulation). Notably, examination of public datasets revealed high levels of IL8 transcripts in HER2-enriched as well as basal-like primary breast tumors, two subtypes characterized by a particularly poor prognosis. Moreover, IL8 expression correlated with high tumor grade and ER-negative status. Importantly, treatment with IL8-neutralizing antibodies prevented invasion of MCF10A-HER2/HER3 and BT474 cells in 3D cultures, highlighting the importance of IL8 autocrine signaling upon HER2/HER3 activation. Our findings demonstrate that HER2 and HER3 co-expression induces IL8 autocrine signaling, leading to the invasion of mammary cells. Agents targeting IL8 or its receptor CXCR1 may be useful for the treatment of HER2/HER3/IL8-positive breast cancers with invasive traits.
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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：
2.3
作者：
Le, XD;Shi, Q;Xie, KP
通讯作者：
Xie, KP
影响因子：
2.2
作者：
Singh, RK;Varney, ML;Johansson, SL
通讯作者：
Johansson, SL
影响因子：
64.8
作者：
Sergina, Natalia V.;Rausch, Megan;Wang, Donghui;Blair, Jimmy;Hann, Byron;Shokat, Kevan M.;Moasser, Mark M.
通讯作者：
Moasser, Mark M.
影响因子：
15.9
作者：
Ginestier, Christophe;Liu, Suling;Wicha, Max S.
通讯作者：
Wicha, Max S.