The Type III Transforming Growth Factor-β Receptor as a Novel Tumor Suppressor Gene in Prostate Cancer

Abstract

The transforming growth factor-B (TGF-B) signaling pathway has an important role in regulating normal prostate epithelium, inhibiting proliferation, differentiation, and both androgen deprivation-induced and androgen-independent apoptosis. During prostate cancer formation, most prostate cancer cells become resistant to these homeostatic effects of TGF-B. Although the loss of expression of either the type I (TBRI) or type II (TBRII) TGF-B receptor has been documented in f30% of prostate cancers, most prostate cancers become TGF-B resistant without mutation or deletion of TBRI, TBRII, or Smads2, 3, and 4, and thus, the mechanism of resistance remains to be defined. Here, we show that type III TGF-B receptor (TBRIII or betaglycan) expression is decreased or lost in the majority of human prostate cancers as compared with benign prostate tissue at both the mRNA and protein level. Loss of TBRIII expression correlates with advancing tumor stage and a higher probability of prostate-specific antigen (PSA) recurrence, suggesting a role in prostate cancer progression. The loss of TBRIII expression is mediated by the loss of heterozygosity at the TGFBR3 genomic locus and epigenetic regulation of the TBRIII promoter. Functionally, restoring TBRIII expression in prostate cancer cells potently decreases cell motility and cell invasion through Matrigel in vitro and prostate tumorigenicity in vivo. Taken together, these studies define the loss of TBRIII expression as a common event in human prostate cancer and suggest that this loss is important for prostate cancer progression through effects on cell motility, invasiveness, and tumorigenicity. [Cancer Res 2007;67(3):1090-8]

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

“…Previous findings have shown that changes in TGFβR3 affect cell homeostasis 2, 18. In the early stage of some tumors, the expression of TGFβR3 is suppressed, and replenishment of TGFβR3 inhibits tumor metastasis, invasion, and growth 19.…”

The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

“…An essential role for T␤RIII has also been demonstrated in mesenchymal transformation during chick embryonic heart development (11, 12) and in mediating TGF-␤ resistance in intestinal goblet cells (13). We have defined essential roles for the cytoplasmic domain of T␤RIII in mediating TGF-␤ signaling independent of the ligand presentation role (14), along with regulating cell-surface levels of T␤RIII and T␤RII through interactions with G␣-interacting protein-interacting protein, C terminus (GIPC) (15) and ␤-arrestin2 (16).Loss of T␤RIII expression has been reported in multiple cancers, with loss of expression correlating with disease progression, advanced stage, or grade and/or a poorer prognosis for patients (17)(18)(19)(20)(21)(22). Importantly, increasing or restoring expression of T␤RIII in these cancer models decreases cancer cell motility and invasion in vitro (17-21) and angiogenesis, invasion, and metastasis in vivo (17).…”

“…Loss of T␤RIII expression has been reported in multiple cancers, with loss of expression correlating with disease progression, advanced stage, or grade and/or a poorer prognosis for patients (17)(18)(19)(20)(21)(22). Importantly, increasing or restoring expression of T␤RIII in these cancer models decreases cancer cell motility and invasion in vitro (17-21) and angiogenesis, invasion, and metastasis in vivo (17).…”

Elevated level of inhibin-α subunit is pro-tumourigenic and pro-metastatic and associated with extracapsular spread in advanced prostate cancer

“…We have shown that LNCaP cells express more TGFbRIII mRNA expression compared to PC3 cells and that the level of TGFbRIII mRNA expression is maintained after INHa over-expression. Loss of TGFbRIII during PCa progression has been suggested to be a reason for loss of sensitivity to the tumour suppressive effect of inhibin in prostate disease (Turley et al, 2007;Sharifi et al, 2007a, b). Whether androgen status, different cell types and/or levels of TGFbRIII expression are responsible for the different effects of inhibin observed in the present study is an important area of future investigation.…”

“…Although being a receptor for TGFb, TGFbRIII is also a receptor for inhibins (Wiater and Vale, 2003), and recent studies have reported loss of TGFbRIII as a common and important event in human PCa (Turley et al, 2007;Sharifi et al, 2007a). Downregulation of TGFbRIII in PCa has been suggested to reflect loss of sensitivity to tumour suppressive inhibin by the PCa cells.…”