title: Decreased tumorigenic potential of EphA2-overexpressing breast cancer cells following treatment with adenoviral vectors that express EphrinA1.
abstract: The EphA2 receptor tyrosine kinase is frequently overexpressed in invasive breast cancer cells. Moreover, these malignant cells have unstable cell-cell contacts, which preclude EphA2 from interacting with its ligand, EphrinA1, which is anchored to the membrane of adjacent cells. This defect is important because ligand binding causes EphA2 to transmit signals that negatively regulate tumor cell growth and survival, whereas the absence of ligand binding favors these same behaviors. In our present study, human adenoviral type 5 (HAd) vectors were engineered to express secreted-forms of EphrinA1. These vectors were used to infect MDA-MB-231 human breast cancer cells, or MCF-10A human breast epithelial cells providing matched controls. Infection with HAd-EphrinA1-Fc (HAd vector expressing extracellular domain of human EphrinA1 attached to Fc portion of human IgG1 heavy chain) caused increased EphA2 activation and turnover and consequently decreased tumor cell viability in soft agar assays. Consistent with this observation, infection of MDA-MB-231 cells with HAd-EphrinA1-Fc prevented tumor formation in xenograft models. Furthermore, therapeutic modeling via intratumoral inoculation revealed that HAd-EphrinA1-Fc significantly inhibited subsequent tumor growth as compared to matched controls. These results suggest that targeting of EphA2 with adenoviral vectors may have therapeutic value.
authors.affiliation: Laboratory of Gene Therapy, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Loren W
authors.initials: LW
authors.lastname: Noblitt
authors.forename: Dinesh S
authors.initials: DS
authors.lastname: Bangari
authors.forename: Shruti
authors.initials: S
authors.lastname: Shukla
authors.forename: Deborah W
authors.initials: DW
authors.lastname: Knapp
authors.forename: Sulma
authors.initials: S
authors.lastname: Mohammed
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kinch
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Mittal
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D036382:Ephrin-A1 / Q000235:genetics*; D005822:Genetic Vectors; D006801:Humans; D015552:Injections, Intralesional; D010766:Phosphorylation; D036104:Receptor, EphA2 / Q000235:genetics*
chemical_list: D036382:Ephrin-A1; D036104:Receptor, EphA2