Functional and Clinical Analysis of the PTEN Tumor Suppressor Gene in Prostate Cancer

摘要

This grant application was focused on understanding the PTEN tumor suppressor gene, both at a functional level and with respect to the extent of PTEN loss in prostate tumors. The aims of this new investigator award were to develop antibody reagents to the protein product (PTEN), to characterize the function of PTEN through the identification of downstream targets, and to determine using immunohistochemistry, the extent to which the PTEN protein was lost in primary tumors. It is now recognized that PTEN is a lipid phosphatase that can antagonize signaling though the phosphoinositide-3 kinasi pathway. Our work, funded by the New Investigator mechanism, showed that PTEN can regulate cell-cycle progression by controlling the passage of cells through the G1 checkpoint. This function of PTEN requires its lipid phosphatase activity and requires that PTEN act upstream of the serine-threonine kinase Akt. This kinase, in the absence of PTEN is constitutively active and recent data in our lab further suggests that cell-cycle regulation is linked to the ability of PTEN to inhibit Akt thereby restoring the function of forkhead transcription factors such as FKHR and FKHRL1. Based on this data, in collaboration with a local biopharmaceutical company, we are working on developing inhibitors of the Akt kinase family. Here, our hypothesis is that PTEN null cells may be exquisitely dependent upon Akt for either proliferation or survival. In collaboration with Dr. Massimo Loda, we studied the expression of the PTEN protein in 127 primary prostate tumors obtained by radical prostatectomy. In these studies we found that loss of PTEN was highly associated with higher Gleason score and with more advanced stage tumors. In total these data highlight the importance of PTEN loss to the development and progression 0 prostate cancer, and the hope that Akt inhibitors will be particularly beneficial in this group of tumors.