Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy
Loren W Noblitt1, Dinesh S Bangari, Shruti Shukla
1Laboratory of Gene Therapy, Purdue University, West Lafayette, Indiana 47907, USA.
Abstract:
EphA2, a receptor tyrosine kinase, is elevated in many invasive human breast cancers, and the majority of EphA2 remains unphosphorylated. The successful attachment of ligand EphrinA1 present on the surface of adjacent cells to EphA2 initiates EphA2 phosphorylation leading to its turnover. In vivo efficacy of various approaches targeting EphA2 for breast cancer therapy is usually evaluated in nude mice bearing human breast cancer xenografts. In order to establish an immunocompetent mouse model of breast cancer for EphA2-targeted therapies, we evaluated a mouse breast cancer cell line (MT1A2) for EphA2 expression and phosphorylation. Overexpression of EphA2 was observed in MT1A2 cells and the majority of it remained unphosphorylated signifying that EphA2 in MT1A2 cells behaved similar to that of human breast cancer cells. Human adenovirus subtype 5 (HAd5) vectors expressing secretory forms of EphrinA1 were used for in vitro and in vivo targeting of MT1A2-derived EphA2. MT1A2 cells infected with HAd-EphrinA1-Fc (HAd expressing extracellular domain of human EphrinA1 attached to Fc portion of human IgG1 heavy chain) induced EphA2 activation and its turnover. This led to inhibition in MT1A2 cell colony formation in soft agar and cell viability in monolayer culture. In addition, MT1A2 cells-infected with HAd-EphrinA1-Fc failed to form tumors in syngeneic FVB/n mice at least 32 days postinoculation. Moreover, intratumoral inoculation of FVB/n mice-bearing MT1A2-induced tumors with HAd-EphrinA1-Fc slowed the tumor growth and also resulted in the development of vector-specific immune response. These results indicate that FVB/n mice-bearing MT1A2-induced tumors could serve as an immunocompetent model of breast cancer for EphA2-targeted therapeutic strategies.
Insights
Researchers developed a new immunocompetent mouse model for breast cancer therapy. This model uses MT1A2 cells and human adenovirus vectors to target EphA2, showing promise for EphA2-targeted treatments.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- EphA2 receptor tyrosine kinase is overexpressed in invasive breast cancers.
- EphA2 phosphorylation, triggered by EphrinA1 ligand binding, leads to its turnover.
- Current EphA2-targeted therapy evaluation often uses nude mice with human breast cancer xenografts.
Purpose of the Study:
- To establish an immunocompetent mouse model for evaluating EphA2-targeted breast cancer therapies.
- To assess the behavior of EphA2 in a mouse breast cancer cell line (MT1A2).
- To investigate the efficacy of targeting EphA2 using human adenovirus subtype 5 (HAd5) vectors expressing EphrinA1.
Main Methods:
- Evaluated EphA2 expression and phosphorylation in MT1A2 mouse breast cancer cells.
- Utilized HAd5 vectors encoding secretory EphrinA1 (HAd-EphrinA1-Fc) for in vitro and in vivo studies.
- Assessed tumor formation, growth inhibition, and immune response in syngeneic FVB/n mice.
Main Results:
- MT1A2 cells exhibited EphA2 overexpression, similar to human breast cancer cells.
- HAd-EphrinA1-Fc treatment activated EphA2, induced its turnover, and inhibited MT1A2 cell proliferation in vitro.
- MT1A2 cells infected with HAd-EphrinA1-Fc failed to form tumors in syngeneic mice, and intratumoral inoculation slowed tumor growth and elicited an immune response.
Conclusions:
- The MT1A2 mouse breast cancer cell line mimics human cancer regarding EphA2 expression and phosphorylation.
- FVB/n mice bearing MT1A2-induced tumors represent a viable immunocompetent model for studying EphA2-targeted breast cancer therapies.
- This model facilitates the investigation of therapeutic strategies involving EphA2 activation and immune-mediated responses.
