Prostate cancer is a leading cause of cancer death in men, with the number of diagnosed cases steadily increasing. In the United States alone, approximately 198,000 men will be diagnosed and 32,000 will die from prostate cancer this year. Despite the successes in identifying predisposition genes and defining genetic pathways in other major cancers, most notably breast and colon cancer, until recently, no major prostate cancer gene(s) had been identified. The identification and characterization of these genes would allow for earlier and more specific diagnostic and prognostic tests and the development of rational treatment strategies. We have recently shown that KLF6 is a gene mutated in a majority of prostate cancers. As we are beginning to understand, KLF6 normally helps to regulate cell growth and differentiation; important processes during the growth, maintenance, and repair of all cells and tissues. In up to 50' of prostate cancers, at least two inactivating events occur in tumor cells that destroy the normal function of the KLF6 gene. These cells would be predicted to be able to grow, divide, and spread uncontrollably. These findings represent an important step toward understanding and eventually treating prostate cancer. Most recently, we have identified a specific KLF6 germline mutation, a DNA sequence change present in the blood of 18.5' of families with an inherited predisposition to prostate cancer. These results suggest that it is possible to identify those individuals with a marked predisposition to the development of prostate cancer by means of a simple blood test years before the cancer would be expected to develop. This proposal intends to clearly define the role of this KLF6 mutation in the development and progression of prostate cancer. To do so, we will examine a larger population of individuals both with and without prostate cancer to validate our preliminary results. In addition, we will begin experiments to define the biologic mechanisms by which this KLF6 mutation results in an increased prostate cancer risk. These experiments will be performed in human cells and also in a mouse model. The mouse will be genetically engineered such that its normal gene will be replaced by the human prostate cancer susceptibility mutation. In this manner, we will be uniquely able to study the in vivo effect of and natural history of this KLF6 mutation. Therefore, the significance of these studies is the potential to immediately develop a blood-based test to identify individuals with an increased prostate cancer risk years before the cancer develops. Moreover, the insights provided by these studies into the genetic basis of prostate cancer may ultimately lead to improved treatment options.