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. IntroductionMalignant progression of solid tumors is a complex process that involves the activation of oncogenic signaling and downregulation of tumor suppressor pathways. In addition, modulation of the tumor microenvironment, for example through neovascularization, enhances tumor cell growth and survival, promoting invasion and metastatic spread (reviewed in refs. 1-3). Oncogenic conversion, amplification, or overexpression of protooncogenes, such as those encoding cell surface receptor tyrosine kinases (RTKs) like the EGF receptor family member ErbB2, are frequently observed in human cancers and contribute to malignancy. Other pathways, such as p53 transcription factor/genome surveillance factor, negatively regulate growth, and loss of these pathway components also contributes to tumorigenesis (reviewed in refs. 3, 4). Recent evidence suggests that Eph RTKs play multiple roles in neoplastic progression, including regulation of processes intrinsic to tumor cells, and in the tumor microenvironment, such as tumor neovascularization (reviewed in refs. 5-8).

BACKGROUND Molecules that are highly expressed by human prostate cancers may serve as therapeutically relevant targets or tumor markers. Tyrosine kinases are frequently overexpressed in metastatic tumor cells and this prompted us to screen for tyrosine kinases that are overexpressed in prostate cancer cells. METHODS Expression levels of the EphA2 receptor tyrosine kinase were determined by Western blot analysis in canine and human prostate cancer cell lines and in immortalized and transformed variants of 267B1 prostatic epithelial cells. EphA2 levels in benign human prostate and prostate cancers were also determined in formalin‐fixed, paraffin‐embedded tissues using immunohistochemical staining. RESULTS Metastatic prostate cancer cells overexpressed EphA2 by 10‐100 fold as compared with non‐invasive prostatic epithelial cells. EphA2 immunoreactivity in vivo was also significantly greater in human prostate cancers as compared with benign prostate epithelium. CONCLUSIONS The EphA2 receptor tyrosine kinase is differentially expressed in human and canine prostate cancer cell lines and overexpressed in human prostate cancers as compared with benign prostate tissues. Metastasis‐derived canine prostate carcinoma cell lines overexpress EphA2 and may provide pre‐clinical models to further evaluate the role of EphA2 in prostate carcinogenesis. Further investigations are needed to determine the utility of EphA2 as a tumor marker and a novel target in human prostate cancer. Prostate 41:275–280, 1999. © 1999 Wiley‐Liss, Inc.

EA5 in combination with paclitaxel decreased tumor growth in an orthotopic ovarian cancer mouse model through antiangiogenic mechanisms associated with reduced levels of VEGF and phosphorylated Src. Humanized antibody constructs against EphA2 are worthy of future study.

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