Tumor suppressor genes in the pathogenesis of prostate cancer: Lessons from mouse models

Prostate cancer, the most frequently diagnosed cancer in American men, is responsible for 30,000 deaths annually. Given the importance of tumor suppressor genes in prostate cancer biology it is no surprise that the most widely used mouse models are based on the disruption of PTEN, TP53 and RB. The role of these three genes in prostate cancer is evaluated in the body of work that composes this dissertation, with emphasis in the connection between morphologic features and underlying genetic lesions as demonstrated in mouse models. The first chapter is a review of loss of heterozygosity (LOH) as one of the main causes of tumor suppressor gene loss. The second chapter describes unique phenotypic outcomes of the disruption of TP53, RB and PTEN in both mice and men. The third chapter focuses on the biology of the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, based on the simultaneous disruption of pRB and p53 proteins by the SV40 T antigen in the mouse prostate. Findings confirm that neuroendocrine carcinomas, arising independently of epithelial lesions, are the main outcome of this model. Chapter 4 provides evidence of the cooperativity between Pten and Trp53 in prostate cancer initiation based on analysis of Pten/Trp53 double heterozygous mice. Lastly, a correlation between lesion progression in Pten heterozygous mouse prostatic tissues and loss of the second allele of Pten is attempted unsuccessfully. The final chapter, therefore, offers a discussion of challenges related to the methods used for LOH detection. In conclusion, the role of the comparative pathologist, combining skillful morphologic evaluation and knowledge of cancer genetics, is underscored in the context of genetically engineered mouse models throughout the dissertation.