Prostate cancer represents a serious health problem for American men since it represents the second leading cause of death from cancer in men, and it is estimated that one out of every nine men will develop prostate cancer. Therefore, it is necessary to spend considerable effort to understand why prostate cancer occurs, and why it is on the rise. If we obtain a better understanding of the molecular pathway that leads to prostate cancer, we will be in a better position to find more rationale strategies for prevention and treatment of this disease.

One of the major difficulties in prostate cancer research has been the long latent period of this disease. In particular, while the initiation of prostate cancer could occur in men as early as their twenties, the clinically detectable cancer generally arises late in life. In this regard, researchers have pursued developing appropriate model systems in the mouse to mimic the progression of human prostate cancer in a relatively short period. However, it is difficult because there have been few molecules that are ¿candidates¿ in the pathway that leads to prostate cancer. We have now identified a new molecule, termed NKX3.1, which we believe to be lost as one of the first steps in the pathway to prostate cancer. Thus, we found that the NKX3.1 lacking mice developed a cancer-like appearance in their prostates, which highly resemble the onset of human prostate cancer. Since NKX3.1 belongs to a category of regulatory molecules that function to control the expression of other genes, we hypothesize that loss of function of NKX3.1 in prostate may lead to altered expression of downstream genes, which thereby promotes the initiation of prostate cancer.

Our plan in this proposal is to use a recently developed technique, termed microarray analysis, to perform a comprehensive gene expression profiling of prostate from NKX3.1 lacking mice relative to that from normal mice, thus identifying genes that are controlled by NKX3.1 in prostate cells. Once we have identified genes that are controlled by NKX3.1, we will determine whether they are altered in human prostate cancer cells. Ultimately, we will investigate whether alterations in these new genes contribute to prostate cancer. Our proposed studies will identify many new genes that are candidate regulatory molecules whose altered expression contribute to prostate cancer and therefore will help to define the molecular events that culminate in prostate carcinoma.