Rats, like humans, vary considerably in susceptibility for mammary cancer development among different strains. The Copenhagen (Cop) rat is extremely resistant to mammary cancer development induced by a variety of carcinogens. Multiple genetic loci have been linked to the resistant phenotype, but the genes have yet to be cloned and the mechanisms underlying the resistance still remain unknown. Transplantation experiments, however, have demonstrated that these genes act only in the epithelial cells of mammary parenchyma; they do not act systemically. In the present study, we analyzed genes differentially expressed in mammary epithelial cells obtained from pubescent female Cop and susceptible Buffalo (Buf) rats, using PCR-based suppressive subtractive hybridization and cDNA microarray approaches. Our results showed a high degree of similarity in the expression profiles of about 4000 genes between Cop and Buf rats, with a few exceptions. We found that the interleukin-2 receptor alpha (IL-2Ralpha) chain gene and claudin-6 gene were preferentially expressed in mammary epithelial cells purified from Cop rats. We further demonstrated that IL-2Ralpha message was undetectable in two rat mammary cancer cell lines and in two human breast cancer cell lines. The level of claudin-6 mRNA was undetectable in two rat mammary cancer cell lines and was lower in two human breast cancer cell lines and one breast cancer sample than that in normal breast tissues. These results suggest that IL-2Ralpha and claudin-6 may function as tumor suppressors, particularly for breast cancer. However, this possibility needs further investigation.