Antiproliferative B cell translocation gene 2 protein is downregulated post-transcriptionally as an early event in prostate carcinogenesis

B cell translocation gene 2 (BTG2) is a p53 target that negatively regulate s cell cycle progression in response to DNA damage and other stress. The ob jective of this study was to examine the expression, regulation and tumor s uppressor properties of BTG2 in prostate cells. By immunohistochemistry BTG 2 protein was detected in similar to 50 % of basal cells in benign glands f rom the peripheral zone of the human prostate. BTG2 was expressed in all hy perproliferative atrophic peripheral zone lesions examined (simple atrophy, post-atrophic hyperplasia and proliferative inflammatory atrophy), but was undetectable or detectable at very low levels in the hyperproliferative ep ithelial cells of HGPIN and prostate cancer. BTG2 mRNA was detected in non- malignant prostate epithelial (PE) cells and in LNCaP cells, but not in PC- 3 cells, consistent with p53-dependent regulation. In PE cells BTG2 protein was detected in areas of cell confluence by immunohistochemistry. BTG2 pro tein in LNCaP cells was undetectable by immunohistochemistry but was detect ed by immunoblotting at 8- to 9-fold lower levels than in PE cells. BTG2 pr otein levels were shown to be regulated by the ubiquitin-proteosome system. Forced expression of BTG2 in PC-3 cells was accompanied by a decreased rat e of cell proliferation and decreased tumorigenicity of these cells in vivo . Taken together, these findings suggest that BTG2 functions as a tumor sup pressor in prostate cells that is activated by cell quiescence, cell growth stimuli as part of a positive feedback mechanism and in response to DNA da mage or other cell stress. The low steady-state levels of BTG2 protein in H GPIN and prostate cancer, a potential consequence of increased protcosomal degradation, may have important implications in the initiation and progress ion of malignant prostate lesions. Furthermore, these findings suggest that a significant component of the p53 G(1) arrest pathway might be inactivate d in prostate cancer even in the absence of genetic mutations in p53.