An Experimental System to Evaluate LOH in Prostate Cancer

Abstract : The goal of this grant is to establish a new biological system for studying the progression of prostate cancer. We propose a technology we have previously developed to help define X-chromosome inactivation to increase our understanding of the molecular biology of prostrate cancer. Using a mouse model, our goal is to induce functional Loss of Heterozygosity (LOH) on a particular chromosome at various specified times during development or life span. Specifically, we plan to induce LOH only in mouse prostatic tissues. We are particularly interested in evaluating sites of allelic loss previously identified to be associated with prostate cancer (7q, 8p, 10p, 10q, 13q, 16q, 18q) in humans and understanding the effect of LOH on syntenic mouse chromosomes. We believe this approach has the potential to increase our knowledge of the acquisition and progression of prostate cancer. A systematic experimental approach for creating LOH can help define new prostate specific tumor suppressor genes. As human chromosome 8p is most frequently associated with prostate cancer (80% of primary and metastatic prostate cancers show this chromosomal variant, our mouse model system will initially focus on the development of those mouse chromosomes syntenic with human chromosome 8p. This technology would augment the positional cytogenetic approach to understanding the genetic complexity of prostate cancer.