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Protection against mammary tumor growth by vaccination with full-length, modified human ErbB-2 DNA

W Z Wei1, W P Shi, A Galy

  • 1Breast Cancer Program, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA. weiw@karmanos.org

International Journal of Cancer
|May 18, 1999
PubMed

Insights

ErbB-2A, a mutant form of ErbB-2 lacking tyrosine kinase activity, shows promise as an anticancer vaccine. This modified protein inhibited tumor growth in mice, suggesting its potential for cancer immunotherapy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • ErbB-2 overexpression is common in human cancers, driving tumor growth via tyrosine kinase activity.
  • The presence of anti-ErbB-2 antibodies and T cells in cancer patients suggests ErbB-2 is a viable target for active cancer vaccination.
  • Developing effective cancer vaccines requires understanding the role of specific protein domains and cellular localization.

Purpose of the Study:

  • To evaluate three mutant ErbB-2 DNA constructs as potential tumor vaccines.
  • To investigate the impact of eliminating tyrosine kinase activity on ErbB-2's vaccine potential.
  • To assess the effect of directing ErbB-2 to the cytoplasm on its stability and immunogenicity.

Main Methods:

  • Generated three ErbB-2 DNA constructs: ErbB-2A (kinase-dead mutant), cyt ErbB-2 (cytoplasmic), and cyt ErbB-2A (cytoplasmic, kinase-dead).
  • Measured protein expression using flow cytometry in transfected D2F2 cells, with and without proteasome inhibitors.
  • Assessed ErbB-2 autophosphorylation via Western blot and evaluated tumor growth inhibition in BALB/c mice post-vaccination.

Main Results:

  • Transmembrane ErbB-2 and ErbB-2A were expressed, while cytoplasmic forms showed rapid degradation without proteasome inhibition.
  • The K to A mutation successfully abolished ErbB-2 autophosphorylation.
  • Vaccination with ErbB-2 or ErbB-2A inhibited ErbB-2-positive tumor growth, unlike cytoplasmic variants.

Conclusions:

  • ErbB-2A, lacking tyrosine kinase activity, is a promising candidate for anticancer vaccination.
  • The study provides valuable tools for dissecting immune responses to ErbB-2 and advancing cancer immunotherapy strategies.

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