Role of Erbin in ErbB2-dependent breast tumor growth
Role of Erbin in ErbB2-dependent breast tumor growth
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Erbin 在 ErbB2 依赖性乳腺肿瘤生长中的作用
DOI：
10.1073/pnas.1407139111
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发表时间：
2014-10-21
影响因子：
11.1
通讯作者：
Mei, Lin
中科院分区：
文献类型：
--
作者：
Tao, Yanmei;Shen, Chengyong;Mei, Lin
ErbB 2（v-erb-b2禽成红细胞白血病病毒癌基因同源物2）在大约25%的乳腺癌中过表达。本研究表明，Erbin，ErbB 2相互作用的蛋白，被认为是作为一种抗肿瘤因子，促进ErbB 2依赖的乳腺癌细胞的增殖和MMTV-neu转基因小鼠的肿瘤发生。相互作用的破坏降低了ErbB 2依赖性增殖，Erbin中PDZ结构域的缺失阻碍了MMTV-neu小鼠中ErbB 2依赖性肿瘤的发展。Erbin与ErbB 2形成复合物，促进其与伴侣蛋白HSP 90的相互作用，从而防止其降解。ErbB 2和Erbin在人乳腺肿瘤组织中的表达相关。因此，这项研究确定了Erbin和ErbB 2的相互作用作为一种新的药物靶点，连接另一个临床分子靶点，HSP 90，在ErbB 2阳性乳腺癌。ErbB 2（v-erb-b2禽成红细胞白血病病毒癌基因同源物2）是ErbB家族的一种受体酪氨酸激酶，在约25%的乳腺癌中过表达。除了响应配体刺激与其他ErbB受体形成异源二聚体之外，ErbB 2可以以配体非依赖性方式被激活。我们在这里报告，Erbin，ErbB 2相互作用的蛋白质，被认为是作为一种抗肿瘤因子，是专门表达在乳腺腔上皮细胞和促进ErbB 2依赖的乳腺癌细胞的增殖和MMTV-neu转基因小鼠的肿瘤发生。破坏它们的相互作用会降低ErbB 2依赖性增殖，Erbin中PDZ结构域的缺失会阻碍MMTV-neu小鼠中ErbB 2依赖性肿瘤的发展。Erbin与ErbB 2形成复合物，促进其与伴侣蛋白HSP 90的相互作用，从而防止其降解。最后，ErbB 2和Erbin在人乳腺肿瘤组织中的表达相关。总之，这些观察结果确立了Erbin作为乳腺肿瘤形成和进展的ErbB 2调节剂。
Significance ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) is overexpressed in around 25% of breast cancers. The present study reveals that Erbin, an ErbB2-interacting protein that was thought to act as an antitumor factor, facilitates ErbB2-dependent proliferation of breast cancer cells and tumorigenesis in MMTV-neu transgenic mice. Disruption of the interaction decreases ErbB2-dependent proliferation, and deletion of the PDZ domain in Erbin hinders ErbB2-dependent tumor development in MMTV-neu mice. Erbin forms a complex with ErbB2, promotes its interaction with the chaperon protein HSP90, and thus prevents its degradation. ErbB2 and Erbin expression correlates in human breast tumor tissues. Thus, this study identifies the interaction of Erbin and ErbB2 as a novel drug target linking another clinical molecular target, HSP90, in ErbB2-positive breast cancer. ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), a receptor tyrosine kinase of the ErbB family, is overexpressed in around 25% of breast cancers. In addition to forming a heterodimer with other ErbB receptors in response to ligand stimulation, ErbB2 can be activated in a ligand-independent manner. We report here that Erbin, an ErbB2-interacting protein that was thought to act as an antitumor factor, is specifically expressed in mammary luminal epithelial cells and facilitates ErbB2-dependent proliferation of breast cancer cells and tumorigenesis in MMTV-neu transgenic mice. Disruption of their interaction decreases ErbB2-dependent proliferation, and deletion of the PDZ domain in Erbin hinders ErbB2-dependent tumor development in MMTV-neu mice. Mechanistically, Erbin forms a complex with ErbB2, promotes its interaction with the chaperon protein HSP90, and thus prevents its degradation. Finally, ErbB2 and Erbin expression correlates in human breast tumor tissues. Together, these observations establish Erbin as an ErbB2 regulator for breast tumor formation and progression.