Distinct ErbB-2-coupled signaling pathways promote mammary tumors with unique pathologic and transcriptional profiles
Distinct ErbB-2-coupled signaling pathways promote mammary tumors with unique pathologic and transcriptional profiles
复制标题
DOI：
10.1158/0008-5472.can-06-4724
复制
发表时间：
2007-08-15
期刊：
影响因子：
11.2
通讯作者：
Muller, William J.
中科院分区：
文献类型：
--
作者：
Schade, Babette;Lam, Sonya H. L.;Muller, William J.
ErbB-2的过度表达和扩增发生在15%到30%的人类浸润性乳腺癌中，与临床预后不良有关。此前，我们已经证明，在受体的细胞质尾部有四个ErbB-2/Neu酪氨酸自动磷酸化位点招募不同的接头蛋白，并足以在体外介导转换信号。其中两个位点，代表生长因子受体结合蛋白2(Grb2；Neu-Yb)和Src同源物和胶原(Se；Neu-YD)结合位点，可以诱导乳腺肿瘤的发生和转移。在这里，我们表明，携带另外两个ErbB-2自动磷酸化位点(Neu-Yc和Neu-Ye)的转基因小鼠会发生转移性乳腺肿瘤。对所有Neu突变小鼠模型的生物学特征的详细比较表明，Neu-YC、Neu-YD和Neu-Ye乳腺肿瘤具有相似的病理和转录特征。相比之下，Neu-YB小鼠模型显示了一种独特的病理，具有高转移潜力，与独特的转录图谱相关，包括促进恶性肿瘤进展的基因，如金属蛋白酶和趋化因子。此外，Neu-YB肿瘤上皮细胞内显示丰富的趋化因子CXCL12/SDF-Iα蛋白水平，这可能反映了该Neu突变小鼠模型的侵袭性。综上所述，这些发现表明，不同的Neu偶联信号通路的激活对Neu诱导的肿瘤的生物学行为有重要影响。
ErbB-2 overexpression and amplification occurs in 15% to 30% of human invasive breast carcinomas associated with poor clinical prognosis. Previously, we have shown that four ErbB-2/Neu tyrosine-autophosphorylation sites within the cytoplasmic tail of the receptor recruit distinct adaptor proteins and are sufficient to mediate transforming signals in vitro. Two of these sites, representing the growth factor receptor binding protein 2 (Grb2; Neu-YB) and the Src homology and collagen (She; Neu-YD) binding sites, can induce mammary tumorigenesis and metastasis. Here, we show that transgenic mice bearing the two other ErbB-2 autophosphorylation sites (Neu-YC and Neu-YE) develop metastatic mammary tumors. A detailed comparison of biological profiles among all Neu mutant mouse models revealed that Neu-YC, Neu-YD, and Neu-YE mammary tumors shared similar pathologic and transcriptional features. By contrast, the Neu-YB mouse model displayed a unique pathology with a high metastatic potential that correlates with a distinct transcriptional profile, including genes that promote malignant tumor progression such as metalloproteinases and chemokines. Furthermore, Neu-YB tumor epithelial cells showed abundant intracellular protein level of the chemokine CXCL12/SDF-I alpha, which may reflect the aggressive nature of this Neu mutant mouse model. Taken together, these findings indicate that activation of distinct Neu-coupled signaling pathways has an important impact on the biological behavior of Neu-induced tumors.