Cellular mechanisms of resistance to mammary tumorigenesis in the Copenhagen rat

grantor: University of TorontoStudies have identified several genes that play a role in susceptibility to human breast cancer. In contrast, little is known about genes conferring resistance to breast cancer. Resistance is difficult to study in humans, but the Copenhagen (Cop) rat is resistant to mammary tumor induction, and provides an excellent model to study this phenomenon. This thesis focuses on mechanisms that may be responsible for resistance of Cop rats to mammary tumorigenesis. Since there was evidence that T-cell immunity may be involved in resistance, I bred Cop rats with athymic, nude rats that are T-cell deficient, then interbred the F1 offspring to produce F2 animals, some of which were athymic with partial Cop background. If T-cell immunity is involved in resistance, then athymic F2 rats would be more susceptible to mammary tumorigenesis than their euthymic littermates. No tumors developed in any of the F2 rats, indicating resistance to mammary tumorigenesis is not T-cell related and that the parental nude strain is also resistant. Next, I examined the cellular structures of mammary glands of Cop and susceptible rats at various times following carcinogen treatment. Preneoplastic lesions known as intraductal proliferations (IDPs) that harbor 'Ha-ras ' mutation were evident in both strains at early time points, but unlike susceptible rats, the IDPs in Cop rats failed to progress into more advanced lesions and instead disappeared. I examined several potential mechanisms that may be responsible for the disappearance of IDPs in Cop rats. Surprisingly, I found that the proliferative index was higher in Cop IDPs than in those of susceptible Wistar-Furth rats at a time when the IDPs in Cop rats were disappearing. There was, however, a concomitant increase in the apoptotic index in the Cop lesions. Finally, I showed that high levels of cyclin D 1 expression may be important in progression from IDPs to more advanced lesions, since this gene was highly expressed in all tumors but only in some IDPs. Furthermore, elevated expression of this gene may be of importance in resistance, since Cop IDPs had lower levels of cyclin D1 than IDPs of susceptible rats.Ph.D