Activation of Stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated Src and survivin expression
Activation of Stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated Src and survivin expression
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DOI：
10.1158/1078-0432.ccr-04-1749
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发表时间：
2006-01-01
影响因子：
11.5
通讯作者：
Muro-Cacho, CA
中科院分区：
文献类型：
--
作者：
Diaz, N;Minton, S;Muro-Cacho, CA
目的：在包括乳腺癌在内的多种肿瘤中已经观察到信号换能器和转录激活因子3 （Stat3）蛋白的组成性激活，并且至少在一定程度上通过防止细胞凋亡来促进肿瘤的发生。在一项研究中，45名高风险乳腺癌患者参加了多西他赛和阿霉素的II期新辅助化疗试验，我们评估了浸润性乳腺癌与匹配的非肿瘤组织中Stat3的激活水平和潜在的相关分子生物标志物。实验设计：利用免疫组织化学和图像分析，我们量化了福尔马林固定、石蜡包埋的侵袭性癌及其配对的非肿瘤实质切片中磷酸化- stat3 （pY-Stat3）、磷酸化- src （pY-Src）、表皮生长因子受体、HER2/neu、Ki-67、雌激素受体、Bcl-2、Bcl-x(L)、Survivin和凋亡的水平。非肿瘤组织和肿瘤组织中的分子生物标志物水平作为连续变量进行分析，具有统计学意义的相关性。结果：免疫组化检测的pY-Stat3和pY-Src活性水平在浸润性癌组织中明显高于非肿瘤组织（P < 0.001）。在肿瘤中，pY-Stat3水平升高与pY-Src和Survivin水平升高相关。部分病理应答者的pY-Stat3水平高于完全病理应答者。在部分病理应答者中，pY-Stat3水平与Survivin表达相关。结论：我们的研究结果表明Stat3和Src活性升高以及Survivin表达在乳腺癌恶性进展中起重要作用。此外，Stat3活性升高与完全病理反应呈负相关。这些发现表明，特定的Stat3或Src抑制剂可以为乳腺癌患者提供临床益处。
Purpose: Constitutive activation of signal transducer and activator of transcription 3 (Stat3) protein has been observed in a wide variety of tumors, including breast cancer, and contributes to oncogenesis at least in part by prevention of apoptosis. In a study of 45 patients with high-risk breast cancer enrolled in a phase II neoadjuvant chemotherapy trial with docetaxel and doxorubicin, we evaluated the levels of Stat3 activation and potentially associated molecular biomarkers in invasive breast carcinoma compared with matched nonneoplastic tissues.Experimental Design: Using immunohistochemistry and image analysis, we quantified the levels of phospho-Stat3 (pY-Stat3), phospho-Src (pY-Src), epidermal growth factor receptor, HER2/neu, Ki-67, estrogen receptor, Bcl-2, Bcl-x(L), Survivin, and apoptosis in formalin-fixed, paraffin-embedded sections from invasive carcinomas and their paired nonneoplastic parenchyma. The levels of molecular biomarkers in nonneoplastic and tumor tissues were analyzed as continuous variables for statistically significant correlations.Results: Levels of activated pY-Stat3 and pY-Src measured by immunohistochemistry were significantly higher in invasive carcinoma than in nonneoplastic tissue (P < 0.001). In tumors, elevated levels of pY-Stat3 correlated with those of pY-Src and Survivin. Levels of pY-Stat3 were higher in partial pathologic responders than in complete pathologic responders. In partial pathologic responders, pY-Stat3 levels correlated with Survivin expression.Conclusions: Our findings suggest important roles for elevated activities of Stat3 and Src, as well as Survivin expression, in malignant progression of breast cancer. Furthermore, elevated Stat3 activity correlates inversely with complete pathologic response. These findings suggest that specific Stat3 or Src inhibitors could offer clinical benefits to patients with breast cancer.