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

The HER-2/neu proto-oncogene is overexpressed in 20-30% of human breast can cers and is associated with high recurrence risk. The oncogenic potential o f 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 imm une-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 th is line develop spontaneous focal mammary tumors by 6 months of age. Transg enic mice immunized intramuscularly with a HER-2 cDNA ligated into the VR10 12 (VICAL) expression vector under the control of the cytomegalovirus promo ter developed significantly fewer spontaneous tumors as compared with mice injected with the empty vector (P < 0.0001) or not injected (P = 0.0006). H owever, 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 xenoge neic 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-dr iven 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 mecha nisms including aspecific and inflammatory immunological responses.