Prevention of spontaneous neu-expressing mammary tumor development in mice transgenic for rat proto-neu by DNA vaccination.
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.
Pupa
S M
SM
Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Milano, Italy.
Invernizzi
A M
AM
Forti
S
S
Di Carlo
E
E
Musiani
P
P
Nanni
P
P
Lollini
P L
PL
Meazza
R
R
Ferrini
S
S
Menard
S
S
D000367:Age Factors; D000818:Animals; D019496:Cancer Vaccines; D003602:Cytotoxicity, Immunologic; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D007115:Immunization Schedule; D007959:Lymphocyte Culture Test, Mixed; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D019444:Vaccines, DNA
D019496:Cancer Vaccines; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D019444:Vaccines, DNA; C000715470:MAS1 protein, human