Prostate cancer is the most predominant cancer in men in the Western world. Only a minority of prostate cancers progress rapidly, spread throughout the body, and lead to death; the vast majority grow more slowly and never produce clinical symptoms. Using a sensitive blood test for a component of the prostate (PSA), we can detect most cancers early in their evolution even before a person is aware of their existence. However, this test does not tell us whether the cancer will progress rapidly or if it will remain indolent. This has created a therapeutic dilemma since rapidly progressing cancers should be treated aggressively while slow growing cancers may require no treatment at all. Thus, one of the most important clinical objectives in prostate cancer research is to develop an effective test that predicts how a tumor, diagnosed early in its evolution, will behave as time progresses. We propose that a test for centrosome defects may accomplish this objective. Centrosomes are cellular organelles required for dividing genetic material (DNA) into daughter cells during cell division and for maintaining cellular organization. Because these same cellular processes are disrupted in prostate cancer, we began to investigate the role of centrosomes in prostate cancer development and progression. This led to the publication of several important findings during the Phase I funding period of this grant. First, we made the exciting discovery that aggressive prostate tumors have severe defects in the centrosomes. More importantly, centrosomes are abnormal in precancerous lesions of the prostate, even before the appearance of the common signs of prostate cancer, suggesting that they may contribute to rather than result from disease progression. Moreover, we could show that an artificial increase in the amount of the centrosome protein, pericentrin, in normal cells induces genetic instability and changes in cell organization that are indistinguishable from those observed in tumor cells. Based on these novel discoveries, our objective is to investigate a previously unexplored mechanism for the development and progression of prostate cancer: that centrosome defects detected in precancerous lesions of the prostate can both predict and contribute to aggressive cancer. We are confident that significant contributions in the areas of prostate cancer progression, detection, and treatment will be realized by investigating this innovative concept. The work described in this proposal has three major aims: (1) to develop new methods to predict which precancerous lesions will progress to fatal cancer; (2) to gain insight into the role of pericentrin and centrosome defects in prostate cancer progression; and (3) to identify novel centrosome markers for high-grade prostate cancer. In Aim 1, we propose to develop a prognostic test for prostate cancer that would enable caretakers to target therapy specifically to individuals who will develop aggressive disease and eliminate unnecessary treatment (and associated morbidity) of those individuals with indolent disease. In Aim 2, we will investigate a possible cause of prostate cancer by constructing prostate epithelial cells that artificially express pericentrin, introducing them into mouse prostate glands, and asking if they can induce prostate cancer. A second approach to Aim 2 will involve prostate-specific expression of the pericentrin gene introduced into mice by a process called transgenics. If successful, these experiments would demonstrate that the pericentrin protein and the centrosome defects it induces play a critical role in prostate cancer progression. Both of these experiments have a high probability of success since we recently showed that pericentrin-expressing cells grow more rapidly than the parent cells in a cell culture assay, which is a good indicator of tumorigenic potential in animals. In Aim 3, we will identify changes in centrosome molecules (known and novel) that are specific for aggressive cancer with the ultimate goal of developing a noninvasive blood test for specifically targeting treatments to patients with aggressive disease. This strategy would also identify new molecular targets for prostate cancer therapy (including pericentrin). These targets could ultimately be exploited to develop treatments that lack side effects inherent in current therapies since centrosome defects are tumor-specific. The unique constitution of our team, a centrosome biologist and a pathologist, provides a unique, integrated, and comprehensive approach to these important issues in prostate cancer.