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1 Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy; 2 Aging Research Center, CeSi, G. d'Annunzio University Foundation; 3 Department of Oncology and Neurosciences, "G. D'Annunzio" University, Chieti, Italy; 4 Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy; and 5 Istituto G. Gaslini and 6 Immuno-pharmacology Unit, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
Requests for reprints: Sylvie Ménard, Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-02-2390-2571; Fax: 39-02-2390-3073; E-mail: sylvie.menard{at}istitutotumori.mi.it.
Plasmid DNA vectors encoding the full-length (VR1012/HER-2-FL) or only the extracellular and transmembrane domains (VR1012/HER-2-ECD-TM) of human (h) HER-2/neu proto-oncogene were used to vaccinate HER-2/neu transgenic mice (N202) engineered to overexpress the rat (r) neu proto-oncogene product (r-p185neu). Both the full-length and the deleted vaccines were significantly (P = 0.0001 and P = 0.06, respectively) more active than the empty vector (VR1012/EV) in preventing and delaying HER-2/neu-driven mammary carcinogenesis. A low-level intratumoral infiltrate of dendritic cells, macrophages, CD8 T cells and polymorphonuclear granulocytes in association with low-level cytokine production was observed, which was not detected in tumors from control mice. Morphologic analyses showed that vaccination with VR1012/HER-2-FL or ECD-TM also efficiently hampered the development of terminal ductal lobular units (TDLU). Analyses of sera from vaccinated mice revealed high titers of antihuman HER-2/neu antibodies, which correlated with the delayed time of tumor onset (P = 0.002). These antibodies did not cross-react with r-p185neu. Nontransgenic mice treated with the vaccines produced autoreactive antibodies targeting mouse (m)-p185neu and showed impaired function of the lactating mammary gland and accelerated involution of the gland after weaning. Together, these data indicate that xenogeneic DNA immunization breaks tolerance against the endogenous m-p185neu, impairing the development of mammary TDLU in which m-p185neu expression is concentrated. The reduction in the number of TDLU decreases the number of glandular structures available for r-p185neu-dependent mammary carcinogenesis, resulting in a significant inhibition of mammary carcinoma development.
Key Words: HER-2/neu • DNA vaccination • autoimmunity • transgenic mice • mammary carcinoma
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