Prostate cancer is the most common adult male cancer and it is expected that over 40,000 men will die from this disease this year. Our long term objectives re to identify factors associated with the prostate's unique propensity to develop cancer and to understand their subsequent heterogeneity with respect to malignant potential, as it exhibits a broad gradient of cancers from slowly growing to rapidly progressive bony metastasis and death. We have recently identified an antigen that is highly expressed in prostate cells, Prostate Specific Membrane antigen, PSM. We have identified PSM as a unique folate hydrolase. We have discovered that in cancers the mRNA encoding the membrane from predominates, while in normal cells the form encoding the cytosolic form predominates. The implications of this finding are that the prostate may be a tissue at risk for microenvironmental """"""""folate deficiency"""""""", and folate deficiency is associated with increased susceptibility to carcinogenesis. In cancer increasingly folate hydrolase activity resides outside the cell, potentially serving as a means to reacquire folate from polygammaglutamated folate being lost by dying cancer cells. As folate deficiency is associated with limited growth potential the ratio expression of these two majors may contribute to the spectrum of growth potential seen with prostate cancer. We propose to further characterize this unique folate hydrolase and its regulation and to define the folate modulation of growth potential of cells expressing different levels of membrane and cytosolic forms of the protein. We also propose to over- express PSM in the mouse prostate to determine how its expression effects the biology of the prostate in situ. We also propose to generate knockouts of murine PSM to ascertain the importance of its expression at other sites which in the mouse is predominantly the kidney and brain.
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