Gene-specific inhibition of breast carcinoma in BALB-neuT mice by active immunization with rat Neu or human ErbB receptors.
Employing the transgenic BALB-neuT mouse tumor model, we explored the in vivo biologic relevance of immunocompetent epitopes shared among the four ErbB receptors. The outcome of neu-mediated tumorigenesis was compared following vaccination with isogeneic normal rat ErbB2/Neu (LTR-Neu) or xenogeneic human ErbB receptors (LTR-EGFR, LTR-ErbB2, LTR-ErbB3 and LTR-ErbB4), each recombinantly expressed in an NIH3T3 murine cell background. Vaccination using rat LTR-Neu at the stage of atypical hyperplasia potently inhibited neu-mediated mammary tumorigenesis. Moreover, all human ErbB receptors specifically interfered with tumor development in BALB-neuT mice. Relative increase in tumor-free survival and reduction in tumor incidence corresponded to structural similarity shared with the etiologic neu oncogene, as rat orthologue LTR-Neu proved most effective followed by the human homologue LTR-ErbB2 and the other three human ErbB receptors. Vaccination resulted in high titer specific serum antibodies, whose tumor-inhibitory effect correlated with cross-reactivity to purified rat Neu extracellular domain in vitro. Furthermore, a T cell response specific for peptide epitopes of rat Neu was elicited in spleen cells of mice immunized with LTR-Neu and was remotely detectable for discrete peptides upon vaccination with LTR-ErbB2 and LTR-EGFR. The most pronounced tumor inhibition by LTR-Neu vaccination was associated with leukocyte infiltrate and tumor necrosis in vivo, while immune sera specifically induced cytotoxicity and apoptosis of BALB-neuT tumor cells in vitro. Our findings indicated that targeted inhibition of neu oncogene-mediated mammary carcinogenesis is conditional upon the immunization schedule and discrete immunogenic epitopes shared to a variable extent by different ErbB receptors.
Masuelli
Laura
L
Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy.
Focaccetti
Chiara
C
Cereda
Vittore
V
Lista
Florigio
F
Vitolo
Domenico
D
Trono
Paola
P
Gallo
Pasquale
P
Amici
Augusto
A
Monaci
Paolo
P
Mattei
Maurizio
M
Modesti
Mauro
M
Forni
Guido
G
Kraus
Matthias H
MH
Muraro
Raffaella
R
Modesti
Andrea
A
Bei
Roberto
R
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019496:Cancer Vaccines; D018572:Disease-Free Survival; D000939:Epitopes / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D013997:Time Factors; D019076:Transgenes
D019496:Cancer Vaccines; D000939:Epitopes; D018719:Erb-b2 Receptor Tyrosine Kinases