The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling
The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling
复制标题
DOI：
10.1172/jci33154
复制
发表时间：
2008-01-01
影响因子：
15.9
通讯作者：
Chen, Jin
中科院分区：
文献类型：
--
作者：
Brantley-Sieders, Dana M.;Zhuang, Guanglei;Chen, Jin
酪氨酸激酶EPH受体A2 （EphA2）的过表达常见于侵袭性乳腺癌，并与预后不良相关。然而，虽然EphA2已被报道在几种模型系统中增强肿瘤发生、增殖和MAPK激活，但其他研究表明，EphA2激活会减弱这些过程，并在配体刺激下抑制MAPK的活性。在本研究中，我们消除了2种转基因乳腺癌小鼠模型中EphA2的表达。在过表达ErbB2（也称为Neu）的乳腺上皮小鼠（MMTV-Neu小鼠）中，EphA2缺乏会损害肿瘤的发生和转移进展，但在过表达多瘤病毒中间T抗原的乳腺上皮小鼠（MMTV-PyV-mT小鼠）中则不会。MMTV-Neu小鼠乳腺上皮的组织学和离体分析表明，EphA2增强了肿瘤的增殖和运动能力。生化分析显示，EphA2在人和小鼠乳腺癌细胞中与ErbB2形成复合物，导致Ras-MAPK信号通路和RhoA GTPase的激活增强。此外，MMTV-Neu肿瘤对EphA2的治疗抑制敏感，而MMTV-PyV-mT则不敏感。这些数据表明EphA2与ErbB2协同促进小鼠肿瘤进展，并可能为人类依赖ErbB2的肿瘤提供新的治疗靶点。此外，EphA2在肿瘤进展中的功能似乎依赖于癌基因背景，这是针对EphA2的治疗应用的重要考虑因素。
overexpression of the receptor tyrosine kinase EPH receptor A2 (EphA2) is commonly observed in aggressive breast cancer and correlates with a poor prognosis. However, while EphA2 has been reported to enhance tumorigenesis, proliferation, and MAPK activation in several model systems, other studies suggest that EphA2 activation diminishes these processes and inhibits the activity of MAPK upon ligand stimulation. In this study, we eliminated EphA2 expression in 2 transgenic mouse models of mammary carcinoma. EphA2 deficiency impaired tumor initiation and metastatic progression in mice overexpressing ErbB2 (also known as Neu) in the mammary epithelium (MMTV-Neu mice), but not in mice overexpressing the polyomavirus middle T antigen in mammary epithelium (MMTV-PyV-mT mice). Histologic and ex vivo analyses of MMTV-Neu mouse mammary epithelium indicated that EphA2 enhanced tumor proliferation and motility. Biochemical analyses revealed that EphA2 formed a complex with ErbB2 in human and murine breast carcinoma cells, resulting in enhanced activation of Ras-MAPK signaling and RhoA GTPase. Additionally, MMTV-Neu, but not MMTV-PyV-mT, tumors were sensitive to therapeutic inhibition of EphA2. These data suggest that EphA2 cooperates with ErbB2 to promote tumor progression in mice and may provide a novel therapeutic target for ErbB2-dependent tumors in humans. Moreover, EphA2 function in tumor progression appeared to depend on oncogene context, an important consideration for the application of therapies targeting EphA2.