A Naturally Occurring HER2 Carboxy-Terminal Fragment Promotes Mammary Tumor Growth and Metastasis
A Naturally Occurring HER2 Carboxy-Terminal Fragment Promotes Mammary Tumor Growth and Metastasis
复制标题
DOI：
10.1128/mcb.01803-08
复制
发表时间：
2009-06-15
影响因子：
5.3
通讯作者：
Arribas, Joaquin
中科院分区：
文献类型：
--
作者：
Pedersen, Kim;Angelini, Pier-Davide;Arribas, Joaquin
HER 2是一种酪氨酸激酶受体，与癌症有因果关系。临床结果特别差的乳腺癌患者亚组表达HER 2羧基末端片段（CTF）的异质性集合。然而，由于CTF缺乏驱动全长HER 2的二聚化和随后活化的细胞外结构域，因此原则上预期它们是无活性的。在这里，我们表明，在低表达水平，这些片段之一，611-CTF，激活多个信号通路，因为它的意外的能力，组成同源二聚体。转录组学分析显示，611-CTF特异性控制我们发现与乳腺癌预后不良相关的基因的表达。在611-CTF调节的基因中，有几个先前与转移有关，包括MET、EPHA 2、基质金属蛋白酶1、白细胞介素11、血管生成素样4和不同的整合素。据认为，乳腺中过表达HER 2的转基因小鼠仅在获得转基因中的激活突变后才发生肿瘤。相比之下，我们发现611-CTF的表达导致了侵袭性和侵袭性乳腺肿瘤的发展，而不需要突变。这些结果表明，611-CTF是一种能够促进乳腺肿瘤进展和转移的有效癌基因。
HER2 is a tyrosine kinase receptor causally involved in cancer. A subgroup of breast cancer patients with particularly poor clinical outcomes expresses a heterogeneous collection of HER2 carboxy-terminal fragments (CTFs). However, since the CTFs lack the extracellular domain that drives dimerization and subsequent activation of full-length HER2, they are in principle expected to be inactive. Here we show that at low expression levels one of these fragments, 611-CTF, activated multiple signaling pathways because of its unanticipated ability to constitutively homodimerize. A transcriptomic analysis revealed that 611-CTF specifically controlled the expression of genes that we found to be correlated with poor prognosis in breast cancer. Among the 611-CTF-regulated genes were several that have previously been linked to metastasis, including those for MET, EPHA2, matrix metalloproteinase 1, interleukin 11, angiopoietin-like 4, and different integrins. It is thought that transgenic mice overexpressing HER2 in the mammary glands develop tumors only after acquisition of activating mutations in the transgene. In contrast, we show that expression of 611-CTF led to development of aggressive and invasive mammary tumors without the need for mutations. These results demonstrate that 611-CTF is a potent oncogene capable of promoting mammary tumor progression and metastasis.