Inhibition of mammary carcinogenesis by systemic interleukin 12 or p185neu DNA vaccination in Her-2/neu transgenic BALB/c mice.

Because BALB/c mice transgenic for the rat Her-2/neu oncogene develop multifocal carcinomas in all mammary glands by week 33, they constitute an aggressive model for investigation of treatments designed to oppose mammary carcinogenesis. Nonspecific immune reaction elicited by systemic interleukin (IL)-12 both delayed the appearance of the first tumor and reduced the number of glands affected. However, only 5% of mice were tumor free at week 33. On the other hand, specific vaccination with plasmids encoding for the rat p185neu resulted in a further delay, so much so that 58% of mice were tumor free at week 33. No CTL response was evoked in either IL-12-treated or DNA-vaccinated mice, whereas an anti-rat p185neu antibody response was evident in the latter. Pathological examinations showed that in both IL-12-treated and DNA-vaccinated mice, the tumor growth area was infiltrated by reactive cells associated with expression of endothelial adhesion molecules and antiangiogenic proinflammatory cytokines. In the vaccinated mice, reduction of the number of cells expressing rat p185neu was combined with down-regulation of its membrane expression and even a marked inhibition in development of the terminal ductal lobular units. The reactive infiltrate in vaccinated mice contained numerous granulocytes that likely played an antiangiogenic and angiodestructive role and also joined other cells in the antibody-mediated killing of the r-p185neu+ cells. These results suggest that the elicitation of nonspecific and specific immunity could be beneficially used in individuals with a high risk of developing tumors.