The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling
Open Access
- 2 January 2008
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 118 (1), 64-78
- https://doi.org/10.1172/jci33154
Abstract
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.Keywords
This publication has 72 references indexed in Scilit:
- Ephrin-A1 Facilitates Mammary Tumor Metastasis through an Angiogenesis-Dependent Mechanism Mediated by EphA Receptor and Vascular Endothelial Growth Factor in MiceCancer Research, 2006
- Expression Profiling of UVB Response in Melanocytes Identifies a Set of p53-Target GenesJournal of Investigative Dermatology, 2006
- Eph receptor signalling casts a wide net on cell behaviourNature Reviews Molecular Cell Biology, 2005
- Cancer genes and the pathways they controlNature Medicine, 2004
- RETRACTED ARTICLE: EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinomaOncogene, 2004
- Activation of the EphA2 tyrosine kinase stimulates the MAP/ERK kinase signaling cascadeOncogene, 2002
- Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosisOncogene, 2001
- The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularizationOncogene, 2000
- The Hallmarks of CancerCell, 2000
- The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patientsEndocrine Reviews, 1992