Gene expression profiling of cancer progression reveals intrinsic regulation of transforming growth factor-β signaling in ErbB2/Neu-induced tumors from transgenic mice
Gene expression profiling of cancer progression reveals intrinsic regulation of transforming growth factor-β signaling in ErbB2/Neu-induced tumors from transgenic mice
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DOI：
10.1038/sj.onc.1208712
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发表时间：
2005-08-01
期刊：
影响因子：
8
通讯作者：
Keri, RA
中科院分区：
文献类型：
--
作者：
Landis, MD;Seachrist, DD;Keri, RA
HER2/ErbB2/Neu的上调发生在15-30%的人类乳腺癌中，并与不良预后相关。ErbB2/Neu转录靶点的确定应有助于开发新的治疗方法。乳腺癌的发展是一个多步骤的过程；因此，为了确定与肿瘤发生发展的不同阶段相关的转录本，我们使用Affymetrix微阵列比较了来自MMTV-Neu转基因小鼠的乳腺癌和癌前乳腺组织的表达谱与野生型乳腺的表达谱。我们确定了324个候选基因，这些基因是ErbB2/Neu诱导的肿瘤相对于野生型对照正常乳腺组织所特有的。与野生型对照相比，这些基因的一个子集(82)在癌前乳腺中的表达也发生了变化，表明它们可能在ErbB2/Neu启动的乳腺肿瘤发生的早期事件中发挥关键作用。对芯片数据的进一步分析显示，几个已知的转化生长因子-β靶基因的表达发生了变化，这表明在ErbB2/Neu诱导的肿瘤中，转化生长因子-β信号级联下调。蛋白印迹分析和免疫组织化学分析证实Smad依赖的Smad1/Alk5和Smad2信号通路在这些肿瘤中是不活跃的。虽然大部分肿瘤中没有磷酸化的Smad2，但在肿瘤的外围存在磷酸化Smad2。有趣的是，磷酸化/激活的Smad2的存在与激活素受体IB/ALK4的表达相关，这表明尽管Smad依赖的转化生长因子-β信号在ErbB2/Neu诱导的肿瘤中缺失，但激活素信号可能在这些肿瘤的前沿活跃。综上所述，这些数据表明，在ErbB2/Neu肿瘤中，转化生长因子-β途径受到内在的抑制，其机制涉及转化生长因子-β受体-I/碱性磷酸酶5的缺失。
Upregulation of HER2/ErbB2/Neu occurs in 15-30% of human breast cancers and correlates with poor prognosis. Identification of ErbB2/Neu transcriptional targets should facilitate development of novel therapeutic approaches. Development of breast cancer is a multistep process; thus, to identify the transcriptomes associated with different stages of progression of tumorigenesis, we compared expression profiles of mammary tumors and preneoplastic mammary tissue from MMTV-Neu transgenic mice to expression profiles of wild-type mammary glands using Affymetrix microarrays. We identified 324 candidate genes that were unique to ErbB2/Neu-induced tumors relative to normal mammary gland tissue from wild-type controls. Expression of a subset of these genes (82) was also changed in the preneoplastic mammary glands compared to wild-type controls, indicating that they may play a pivotal role during early events of ErbB2/Neu-initiated mammary tumorigenesis. Further analysis of the microarray data revealed that expression of several known transforming growth factor (TGF)-beta target genes was altered, suggesting that the TGF-beta signaling cascade is downregulated in ErbB2/Neu-induced tumors. Western blot analysis for TGF-beta-Receptor-I/ALK5 and immunohistochemistry for TGF-beta-Receptor-I/ALK5 and phosphorylated/activated Smad2 confirmed that the Smad-dependent TGF-beta signaling cascade was inactive in these tumors. Although absent in most of the tumor, phosphorylated Smad2 was present in the periphery of tumors. Interestingly, presence of phosphorylated/ activated Smad2 correlated with expression of Activin-Receptor-IB/ALK4, suggesting that although Smad-dependent TGF-beta signaling is absent in ErbB2/Neu-induced tumors, Activin signaling may be active at the leading edge of these tumors. Cumulatively, these data indicate that the TGF-beta pathway is intrinsically suppressed in ErbB2/Neu tumors via a mechanism involving loss of TGF-beta-Receptor-I/ALK5.