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PMID: 17160136 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

The type III TGF-beta receptor suppresses breast cancer progression.

The Journal of clinical investigation ·Vol. 117 ·No. 1 ·2007-01-00 ·Pages 206-17

Dong M, How T, Kirkbride KC, Gordon KJ, Lee JD, Hempel N, Kelly P, Moeller BJ, Marks JR, Blobe GC

Abstract

The TGF-beta signaling pathway has a complex role in regulating mammary carcinogenesis. Here we demonstrate that the type III TGF-beta receptor (TbetaRIII, or betaglycan), a ubiquitously expressed TGF-beta coreceptor, regulated breast cancer progression and metastasis. Most human breast cancers lost TbetaRIII expression, with loss of heterozygosity of the TGFBR3 gene locus correlating with decreased TbetaRIII expression. TbetaRIII expression decreased during breast cancer progression, and low TbetaRIII levels predicted decreased recurrence-free survival in breast cancer patients. Restoring TbetaRIII expression in breast cancer cells dramatically inhibited tumor invasiveness in vitro and tumor invasion, angiogenesis, and metastasis in vivo. TbetaRIII appeared to inhibit tumor invasion by undergoing ectodomain shedding and producing soluble TbetaRIII, which binds and sequesters TGF-beta to decrease TGF-beta signaling and reduce breast cancer cell invasion and tumor-induced angiogenesis. Our results indicate that loss of TbetaRIII through allelic imbalance is a frequent genetic event during human breast cancer development that increases metastatic potential.

MeSH Terms
Animals Disease Models, Animal Disease Progression Female Gene Expression Regulation, Neoplastic Humans Mammary Neoplasms, Animal/genetics,pathology,prevention & control Mice Neoplasm Invasiveness Neoplasm Metastasis Proteoglycans/genetics,physiology Receptors, Transforming Growth Factor beta/genetics,physiology Signal Transduction
Chemicals
Proteoglycans Receptors, Transforming Growth Factor beta betaglycan
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Dong Mei
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
How Tam
Kirkbride Kellye C
Gordon Kelly J
Lee Jason D
Hempel Nadine
Kelly Patrick
Moeller Benjamin J
Marks Jeffrey R
Blobe Gerard C
References (46)
46 references, click to expand
  1. Deletion mapping of chromosomal region 1p32-pter in primary breast cancer.
    Genes Chromosomes Cancer. 1999 Mar;24(3):255-63 PMID: 10451706
  2. Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling.
    Science. 2003 Sep 5;301(5638):1394-7 PMID: 12958365
  3. Cloning the promoter for transforming growth factor-beta type III receptor. Basal and conditional expression in fetal rat osteoblasts.
    J Biol Chem. 1999 Oct 22;274(43):30487-94 PMID: 10521429
  4. Silencing of the mammary-derived growth inhibitor (MDGI) gene in breast neoplasms is associated with epigenetic changes.
    Cancer Res. 1996 Nov 1;56(21):4865-70 PMID: 8895735
  5. Ectodomain cleavage and shedding of the type III transforming growth factor-beta receptor in lung membranes effect of temperature, ligand binding and membrane solubilization.
    Eur J Biochem. 1999 May;261(3):618-28 PMID: 10215877
  6. Chromosome 1 alterations in breast cancer: allelic loss on 1p and 1q is related to lymphogenic metastases and poor prognosis.
    Genes Chromosomes Cancer. 1992 Nov;5(4):311-20 PMID: 1283319
  7. Nontransgenic models of breast cancer.
    Breast Cancer Res. 2000;2(5):331-4 PMID: 11250725
  8. Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft.
    Cancer Res. 2002 Aug 15;62(16):4690-5 PMID: 12183427
  9. Immunohistochemical staining for transforming growth factor beta 1 associates with disease progression in human breast cancer.
    Cancer Res. 1992 Dec 15;52(24):6949-52 PMID: 1458485
  10. Membrane-anchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-beta.
    J Cell Biol. 1989 Dec;109(6 Pt 1):3137-45 PMID: 2592419
  11. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer.
    Cancer Res. 1995 Dec 1;55(23):5548-50 PMID: 7585632
  12. Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines.
    Cancer Res. 1998 Apr 1;58(7):1486-93 PMID: 9537252
  13. Expression of transforming growth factor beta type III receptor suppresses tumorigenicity of human breast cancer MDA-MB-231 cells.
    J Biol Chem. 1997 Oct 3;272(40):25367-72 PMID: 9312157
  14. Correlation between plasma transforming growth factor-beta 1 and second primary breast cancer in a chemoprevention trial.
    Eur J Cancer. 1998 Jun;34(7):999-1003 PMID: 9849446
  15. Extracellular domain of TGFbeta type III receptor inhibits angiogenesis and tumor growth in human cancer cells.
    Oncogene. 2002 May 16;21(22):3541-51 PMID: 12032856
  16. Repeated observation of breast tumor subtypes in independent gene expression data sets.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23 PMID: 12829800
  17. Role of transforming growth factor Beta in human cancer.
    J Clin Oncol. 2005 Mar 20;23(9):2078-93 PMID: 15774796
  18. Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation.
    EMBO J. 1993 May;12(5):1835-45 PMID: 8491177
  19. Gene expression profiling predicts clinical outcome of breast cancer.
    Nature. 2002 Jan 31;415(6871):530-6 PMID: 11823860
  20. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart.
    Science. 1999 Mar 26;283(5410):2080-2 PMID: 10092230
  21. Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency.
    Nat Med. 1998 Jul;4(7):802-7 PMID: 9662371
  22. Functional roles for the cytoplasmic domain of the type III transforming growth factor beta receptor in regulating transforming growth factor beta signaling.
    J Biol Chem. 2001 Jul 6;276(27):24627-37 PMID: 11323414
  23. Genomic profiling identifies alterations in TGFbeta signaling through loss of TGFbeta receptor expression in human renal cell carcinogenesis and progression.
    Oncogene. 2003 Sep 11;22(39):8053-62 PMID: 12970754
  24. Autocrine TGFbeta supports growth and survival of human breast cancer MDA-MB-231 cells.
    Oncogene. 2002 Oct 24;21(49):7514-23 PMID: 12386814
  25. Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites.
    J Cell Biol. 1994 Feb;124(4):557-68 PMID: 8106553
  26. TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression.
    J Clin Invest. 2003 Oct;112(7):1116-24 PMID: 14523048
  27. Loss of heterozygosity at chromosome 1p in different solid human tumours: association with survival.
    Br J Cancer. 1999 Mar;79(9-10):1468-74 PMID: 10188892
  28. Expression of transforming growth factor beta (TGFbeta) type III receptor restores autocrine TGFbeta1 activity in human breast cancer MCF-7 cells.
    J Biol Chem. 1997 May 9;272(19):12862-7 PMID: 9139748
  29. Loss of heterozygosity, allele silencing and decreased expression of p73 gene in breast cancers: prevalence of alterations in inflammatory breast cancers.
    Oncogene. 2000 Nov 9;19(47):5413-8 PMID: 11103943
  30. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer.
    Lancet. 2005 Feb 19-25;365(9460):671-9 PMID: 15721472
  31. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world.
    J Clin Oncol. 2006 May 10;24(14):2137-50 PMID: 16682732
  32. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.
    Science. 1996 Jan 19;271(5247):350-3 PMID: 8553070
  33. Transforming growth factor beta 1 in ductal carcinoma in situ and invasive carcinomas of the breast.
    Eur J Cancer. 1992;28(2-3):641-4 PMID: 1317202
  34. Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study.
    Cancer Res. 2002 Jan 15;62(2):497-505 PMID: 11809701
  35. Immunocytochemical localization of secreted transforming growth factor-beta 1 to the advancing edges of primary tumors and to lymph node metastases of human mammary carcinoma.
    Am J Pathol. 1993 Aug;143(2):381-9 PMID: 8393616
  36. Betaglycan presents ligand to the TGF beta signaling receptor.
    Cell. 1993 Jul 2;73(7):1435-44 PMID: 8391934
  37. Heart and liver defects and reduced transforming growth factor beta2 sensitivity in transforming growth factor beta type III receptor-deficient embryos.
    Mol Cell Biol. 2003 Jun;23(12):4371-85 PMID: 12773577
  38. Mammary tumor suppression by transforming growth factor beta 1 transgene expression.
    Proc Natl Acad Sci U S A. 1995 May 9;92(10):4254-8 PMID: 7753792
  39. Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1.
    Genes Dev. 1993 Dec;7(12A):2308-17 PMID: 8253379
  40. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen.
    Cancer Cell. 2004 Jun;5(6):607-16 PMID: 15193263
  41. Prognostic significance of TGF beta 1 and TGF beta 3 in human breast carcinoma.
    Anticancer Res. 2000 Nov-Dec;20(6B):4413-8 PMID: 11205281
  42. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8430-5 PMID: 12808151
  43. TGF-beta signal transduction.
    Annu Rev Biochem. 1998;67:753-91 PMID: 9759503
  44. The transcriptional repressor Snail promotes mammary tumor recurrence.
    Cancer Cell. 2005 Sep;8(3):197-209 PMID: 16169465
  45. Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors.
    Cancer Res. 2004 Dec 15;64(24):9002-11 PMID: 15604265
  46. A novel mechanism for regulating transforming growth factor beta (TGF-beta) signaling. Functional modulation of type III TGF-beta receptor expression through interaction with the PDZ domain protein, GIPC.
    J Biol Chem. 2001 Oct 26;276(43):39608-17 PMID: 11546783
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI29293
Published
2007-01-00
Epub
2006-00-07
Pages
206-17
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1679965
Subset
IM
Grants
NCI NIH HHS · R01 CA106307 · United States
NCI NIH HHS · R01-CA106307 · United States
External Links
PubMed source DOI: 10.1172/JCI29293 PMC Full Text View journal details
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