Prostate cancer is the second most common cause of cancer deaths in men in the United States. In particular, the terminal metastatic and hormone refractory stage poses tremendous difficulty for clinicians to manage. Consequently, the majority of prostate cancer mortality is contributed by patients with the advanced metastatic stage of disease. The lack of effective treatment for metastatic disease is due to poor understanding of its biology and shortage of appropriate animal models. The main focus of this proposed project is to initiate the investigation of the molecular mechanism that might control the metastatic process in several useful models of metastatic prostate cancer.

We have generated several LAPC human prostate cancer tumors (xenograft models developed in Los Angeles) marked with a light-producing gene. This modification allows easy tracking of the tumor cells in living animals using a very sensitive optical imaging system (charge-coupled device, CCD camera). Interestingly, we observed that different models originally derived from different patients exhibit a wide range of metastatic potential. We plan to investigate a pair of intriguing master gene regulatory proteins named EZH2 and EED. They belong to a large polycomb protein family, which was initially defined as important in maintaining proper development in fruitflies. Not only do the mammalian counterparts of the polycomb proteins exist, they also appear to play critical roles in development and maintaining cell type identity. One of the most important findings in the last year is the discovery that EZH2 protein is expressed at a higher level in metastatic cancer. Moreover, increased EZH2 expression is associated with poor disease outcome. However, the mechanism of EZH2 action in metastatic disease is not known at this time.

Our approach in this study is to investigate the role of EZH2 and its partner EED by perturbing their expression up and down using advance molecular techniques. We anticipate that if the two proteins are involved in this key cancer dissemination process, we would be able to observe the effects of the perturbation in living animals by noninvasive imaging. This project, if successful, will open the door to many in-depth investigations of basic biology as well as the development and testing of novel therapeutic approaches that could target the central command of the metastatic process.