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

Abstract

B cell translocation gene 2 (BTG2) is a p53 target that negatively regulates cell cycle progression in response to DNA damage and other stress. The objective of this study was to examine the expression, regulation and tumor suppressor properties of BTG2 in prostate cells. By immunohistochemistry BTG2 protein was detected in approximately 50% of basal cells in benign glands from the peripheral zone of the human prostate. BTG2 was expressed in all hyperproliferative 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 epithelial 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 protein in LNCaP cells was undetectable by immunohistochemistry but was detected by immunoblotting at 8- to 9-fold lower levels than in PE cells. BTG2 protein levels were shown to be regulated by the ubiquitin-proteosome system. Forced expression of BTG2 in PC-3 cells was accompanied by a decreased rate of cell proliferation and decreased tumorigenicity of these cells in vivo. Taken together, these findings suggest that BTG2 functions as a tumor suppressor in prostate cells that is activated by cell quiescence, cell growth stimuli as part of a positive feedback mechanism and in response to DNA damage or other cell stress. The low steady-state levels of BTG2 protein in HGPIN and prostate cancer, a potential consequence of increased proteosomal degradation, may have important implications in the initiation and progression of malignant prostate lesions. Furthermore, these findings suggest that a significant component of the p53 G(1) arrest pathway might be inactivated in prostate cancer even in the absence of genetic mutations in p53.

Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer

“…BTG2 expression has previously been reported to be lost or reduced in several cancers, including breast and PCs (Ficazzola et al, 2001;Mo¨llerstro¨m et al, 2010). In PC, BTG2 downregulation has been suggested to be an early event (Ficazzola et al, 2001). Although the most striking finding was the loss of expression in CRPC, we also found reduced expression of BTG2 in a subset of PC specimens.…”

“…The loss of BTG2 expression was also significantly associated with a short, cancer progression-free period in prostatectomy-treated patients, suggesting that BTG2 is a putative biomarker of PC aggressiveness. BTG2 expression has previously been reported to be lost or reduced in several cancers, including breast and PCs (Ficazzola et al, 2001;Mo¨llerstro¨m et al, 2010). In PC, BTG2 downregulation has been suggested to be an early event (Ficazzola et al, 2001).…”

Expression of the NF-κB-responsive gene BTG2 is aberrantly regulated in breast cancer

“…In highgrade prostatic intraepithelial neoplasia, which are considered to be probable precursor lesions for a subset of prostate cancers, BTG2 expression was either absent or limited to weak cytoplasmic expression suggesting that loss of BTG2 expression may be an early event in prostate cancer progression. BTG2 expression was also undetectable in higher grade tumors and in bone metastases (Ficazzola et al, 2001). Furthermore, thymic …”

“…The characterization of the rabbit anti-BTG2 antibody has been described (Ficazzola et al, 2001). Expression of BTG2 protein in COS and MCF7 cells was analysed by Western blot using a rabbit anti-BTG2 antibody according to the protocol described .…”

TIS21 /BTG2/PC3 as a link between ageing and cancer: cell cycle regulator and endogenous cell death molecule

“…We earlier reported that mRNA of TIS21 was lost in the thymic carcinoma tissues, whereas the expression was very high and constitutive in mouse thymus, suggesting a potential role of TIS21 during carcinogenesis in thymus (Lim et al 1995). Interestingly, the constitutive expression of TIS21 mRNA in renal proximal tubule and prostate acini was lost in the renal cell carcinoma (Struckmann et al 2004) and the early stage of carcinogenesis in prostate (Ficazzola et al 2001), respectively. It is of an interest to note that Pin1 is a potential target for recurrent prostate cancer treatment (Ayala et al 2003;Ryo et al 2005) and one of the binding proteins of TIS21, when U937 tumor cells were stimulated by EGF (Hong et al 2005).…”