Decreased tumorigenic potential of EphA2-overexpressing breast cancer cells following treatment with adenoviral vectors that express EphrinA1

Loren W. Noblitt, Dinesh S. Bangari, Shruti Shukla, Deborah W. Knapp, Sulma Mohammed, Michael S. Kinch, Suresh K. Mittal

Research output: Contribution to journalArticle

92 Scopus citations

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 IgC1 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.

Original languageEnglish
Pages (from-to)757-766
Number of pages10
JournalCancer gene therapy
Volume11
Issue number11
DOIs
StatePublished - Nov 1 2004
Externally publishedYes

Keywords

  • Adenoviral vectors
  • Breast cancer
  • Delivery vehicle
  • EphA2
  • EphrinA 1

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