Resistance to mammary carcinogenesis in Copenhagen rats: potential roles of vascular endothelial growth factor and mast cells

The Copenhagen (COP) rat is extremely resistant to mammary cancer induction by carcinogens. Multiple genetic loci have been linked to the resistant phenotype, but the mechanisms underlying the resistance still remain unknown. Evidence has shown that the acquisition of angiogenic capacity is critical for tumor development. We, therefore, decided to investigate whether administration of angiogenic factor would enhance mammary carcinogenesis in the COP rat. Vascular endothelial growth factor (VEGF) was administered in a sustained releasing formula to pubescent female COP rats 2 weeks after N-nitroso-N-methylurea (NMU) treatment. Six months after NMU exposure, we found no difference in mammary tumor incidence between VEGF treated animals and controls. Analysis of VEGF expression, however, revealed different expression patterns in mammary epithelial cells of various origins. Mammary epithelial cells from pubescent susceptible Buffalo (BUF) and COP rats expressed substantial levels of VEGF messages, whereas cells prepared from 230-day-old rats showed negligible levels of VEGF mRNA. We also demonstrated that mammary epithelial cells from tumors developed in susceptible BUF rats expressed VEGF, whereas VEGF messages were barely detectable in tumors induced in COP rats. Furthermore, enlargement of the intramammary lymph nodes with prominent mast cells was observed in NMU treated COP rats, but not in NMU treated BUF rats. These results suggest that down regulation of VEGF expression is insufficient for resistance to mammary carcinogenesis, and that enhanced immune response, as evidenced by intramammary lymph node enlargement with mast cell accumulation, may also play a role in conferring resistance in the COP rat.