Brantley-Sieders Dana M, Zhuang Guanglei, Hicks Donna, Fang Wei Bin, Hwang Yoonha, Cates Justin M M, Coffman Karen, Jackson Dowdy, Bruckheimer Elizabeth, Muraoka-Cook Rebecca S, Chen Jin
Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
J Clin Invest. 2008 Jan;118(1):64-78. doi: 10.1172/JCI33154.
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.
受体酪氨酸激酶EPH受体A2（EphA2）的过表达在侵袭性乳腺癌中普遍存在，且与预后不良相关。然而，虽然在多个模型系统中已报道EphA2可增强肿瘤发生、增殖及丝裂原活化蛋白激酶（MAPK）激活，但其他研究表明，EphA2激活会减少这些过程，并在配体刺激时抑制MAPK活性。在本研究中，我们在两种转基因小鼠乳腺癌模型中消除了EphA2表达。EphA2缺陷损害了乳腺上皮中过表达ErbB2（也称为Neu）的小鼠（MMTV-Neu小鼠）的肿瘤起始和转移进程，但在乳腺上皮中过表达多瘤病毒中T抗原的小鼠（MMTV-PyV-mT小鼠）中没有这种情况。对MMTV-Neu小鼠乳腺上皮的组织学和体外分析表明，EphA2增强了肿瘤增殖和运动性。生化分析显示，EphA2在人及小鼠乳腺癌细胞中与ErbB2形成复合物，导致Ras-MAPK信号传导和RhoA GTP酶的激活增强。此外，MMTV-Neu肿瘤对EphA2的治疗性抑制敏感，而MMTV-PyV-mT肿瘤则不敏感。这些数据表明，EphA2与ErbB2协同促进小鼠肿瘤进展，可能为人类ErbB2依赖性肿瘤提供新的治疗靶点。此外，EphA2在肿瘤进展中的功能似乎取决于癌基因背景，这是应用靶向EphA2疗法时的一个重要考虑因素。
