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Prevention of spontaneous neu-expressing mammary tumor development in mice transgenic for rat proto-neu by DNA vaccination

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Abstract

The HER-2/neu proto-oncogene is overexpressed in 20–30% of human breast cancers and is associated with high recurrence risk. The oncogenic potential of HER-2/neu, together with its elevated expression in tumors, cell surface localization, and immunogenicity in some patients, make this oncoprotein an ideal target for immunotherapeutic approaches. To test the efficacy of immune-based strategies in eliciting an antitumor response, we used the N#202 transgenic mouse model engineered to overexpress the rat neu proto-oncogene under the control of the mouse mammary tumor virus promoter; females of this line develop spontaneous focal mammary tumors by 6 months of age. Transgenic mice immunized intramuscularly with a HER-2 cDNA ligated into the VR1012 (VICAL) expression vector under the control of the cytomegalovirus promoter developed significantly fewer spontaneous tumors as compared with mice injected with the empty vector (P < 0.0001) or not injected (p = 0.0006). However, this protection was observed only when immunization was started in 3-month-old but not in 6-month-old mice. These data suggest that the xenogeneic HER-2 DNA sequence can break immune tolerance to rat neu in transgenic N#202 mice and induce protective immunity that impairs the neu oncogene-driven progression of mammary carcinogenesis. The preventive effect achieved by our immunological approach appeared not to be based on anti-neu specific B and T cell immune attacks but was more possibly based on different mechanisms including aspecific and inflammatory immunological responses.

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Acknowledgements

This work was supported by Associazione Italiana per la Ricerca sul Cancro. We thank Laura Mameli for manuscript preparation and Fabio Turatti and Fabio Castiglioni for graphic assistance.

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Authors and Affiliations

  1. Department of Experimental Oncology, Molecular Targeting Unit, Istituto Nazionale Tumori, Milano, Italy

    SM Pupa, AM Invernizzi, S Forti & S Ménard

  2. Department of Oncology and Neurosciences, University ‘G D'Annunzio’, Chieti, Italy

    E Di Carlo & P Musiani

  3. Institute for Cancer Research, University of Bologna, Bologna, Italy

    P Nanni & PL Lollini

  4. Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy

    R Meazza & S Ferrini

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  1. SM Pupa
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  2. AM Invernizzi
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  10. S Ménard
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Pupa, S., Invernizzi, A., Forti, S. et al. Prevention of spontaneous neu-expressing mammary tumor development in mice transgenic for rat proto-neu by DNA vaccination. Gene Ther 8, 75–79 (2001). https://doi.org/10.1038/sj.gt.3301360

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