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Cell, Tumor, and Stem Cell Biology |
Departments of 1 Medicine, 2 Pharmacology and Cancer Biology, and 3 Pathology, Duke University Medical Center, Durham, North Carolina
Requests for reprints: Gerard C. Blobe, 221B MSRB Research Drive, Box 2631, Duke University Medical Center, Durham, NC 27710. Phone: 919-668-1352; Fax: 919-668-2458; E-mail: blobe001{at}mc.duke.edu.
The transforming growth factor-ß (TGF-ß) 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-ß. Although the loss of expression of either the type I (TßRI) or type II (TßRII) TGF-ß receptor has been documented in 
30% of prostate cancers, most prostate cancers become TGF-ß resistant without mutation or deletion of TßRI, TßRII, or Smads2, 3, and 4, and thus, the mechanism of resistance remains to be defined. Here, we show that type III TGF-ß receptor (TßRIII 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 TßRIII 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 TßRIII expression is mediated by the loss of heterozygosity at the TGFBR3 genomic locus and epigenetic regulation of the TßRIII promoter. Functionally, restoring TßRIII 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 TßRIII 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]
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K. J. Gordon, K. C. Kirkbride, T. How, and G. C. Blobe Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2 Carcinogenesis, February 1, 2009; 30(2): 238 - 248. [Abstract] [Full Text] [PDF]
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 E. C. Finger, N. Y. Lee, H.-j. You, and G. C. Blobe Endocytosis of the Type III Transforming Growth Factor-{beta} (TGF-{beta}) Receptor through the Clathrin-independent/Lipid Raft Pathway Regulates TGF-{beta} Signaling and Receptor Down-regulation J. Biol. Chem., December 12, 2008; 283(50): 34808 - 34818. [Abstract] [Full Text] [PDF]
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 V. Margulis, T. Maity, X.-Y. Zhang, S. J. Cooper, J. A. Copland, and C. G. Wood Type III Transforming Growth Factor-{beta} (TGF-{beta}) Receptor Mediates Apoptosis in Renal Cell Carcinoma Independent of the Canonical TGF-{beta} Signaling Pathway Clin. Cancer Res., September 15, 2008; 14(18): 5722 - 5730. [Abstract] [Full Text] [PDF]
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 E. V. Verona, Y. Tang, T. K. Millstead, A. P. Hinck, J. K. Agyin, and L.-Z. Sun Expression, purification and characterization of BGERII: a novel pan-TGF{beta} inhibitor Protein Eng. Des. Sel., July 1, 2008; 21(7): 463 - 473. [Abstract] [Full Text] [PDF]
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N. Hempel, T. How, S. J. Cooper, T. R. Green, M. Dong, J. A. Copland, C. G. Wood, and G. C. Blobe Expression of the type III TGF-{beta} receptor is negatively regulated by TGF-{beta} Carcinogenesis, May 1, 2008; 29(5): 905 - 912. [Abstract] [Full Text] [PDF]
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K. C. Kirkbride, T. A. Townsend, M. W. Bruinsma, J. V. Barnett, and G. C. Blobe Bone Morphogenetic Proteins Signal through the Transforming Growth Factor-{beta} Type III Receptor J. Biol. Chem., March 21, 2008; 283(12): 7628 - 7637. [Abstract] [Full Text] [PDF]
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E. C. Finger, R. S. Turley, M. Dong, T. How, T. A. Fields, and G. C. Blobe T{beta}RIII suppresses non-small cell lung cancer invasiveness and tumorigenicity Carcinogenesis, March 1, 2008; 29(3): 528 - 535. [Abstract] [Full Text] [PDF]
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K. J. Gordon, M. Dong, E. M. Chislock, T. A. Fields, and G. C. Blobe Loss of type III transforming growth factor {beta} receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression Carcinogenesis, February 1, 2008; 29(2): 252 - 262. [Abstract] [Full Text] [PDF]
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H. J. You, M. W. Bruinsma, T. How, J. H. Ostrander, and G. C. Blobe The type III TGF- receptor signals through both Smad3 and the p38 MAP kinase pathways to contribute to inhibition of cell proliferation Carcinogenesis, December 1, 2007; 28(12): 2491 - 2500. [Abstract] [Full Text] [PDF]
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 N. Sharifi, R. J Lechleider, and W. L Farrar Transforming growth factor-{beta} receptor III downregulation in prostate cancer: is inhibin B a tumor suppressor in prostate? J. Mol. Endocrinol., November 1, 2007; 39(5): 329 - 332. [Abstract] [Full Text] [PDF]
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T. L. McCarthy, T. H. Pham, B. I. Knoll, and M. Centrella Prostaglandin E2 Increases Transforming Growth Factor-{beta} Type III Receptor Expression through CCAAT Enhancer-Binding Protein {delta} in Osteoblasts Mol. Endocrinol., November 1, 2007; 21(11): 2713 - 2724. [Abstract] [Full Text] [PDF]
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N. Hempel, T. How, M. Dong, S. K. Murphy, T. A. Fields, and G. C. Blobe Loss of Betaglycan Expression in Ovarian Cancer: Role in Motility and Invasion Cancer Res., June 1, 2007; 67(11): 5231 - 5238. [Abstract] [Full Text] [PDF]
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