The type III TGF-β receptor suppresses breast cancer progression
Mei Dong, … , Jeffrey R. Marks, Gerard C. Blobe
Mei Dong, … , Jeffrey R. Marks, Gerard C. Blobe
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):206-217. https://doi.org/10.1172/JCI29293.
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The type III TGF-β receptor suppresses breast cancer progression

Abstract

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

Authors

Mei Dong, Tam How, Kellye C. Kirkbride, Kelly J. Gordon, Jason D. Lee, Nadine Hempel, Patrick Kelly, Benjamin J. Moeller, Jeffrey R. Marks, Gerard C. Blobe

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Figure 7

Restoration of TβRIII expression inhibits Matrigel invasiveness of MDA-MB231 breast cancer cells.

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Restoration of TβRIII expression inhibits Matrigel invasiveness of MDA-M...
(A) MDA-MB231 cells were infected with equivalent amounts of adenoviral constructs carrying GFP, HA-tagged TβRIII, and a TβRIII mutant lacking the entire cytoplasmic domain (TβRIIIΔcyto). Expression of the transgenes was confirmed by Western blotting of cell lysate using anti-HA antibody. (B and C) Matrigel invasion assay. Adenovirally infected MDA-MB231 cells (75,000 cells) were seeded in a Matrigel-coated upper chamber and treated with TGF-β1 (15 pM) 2 hours later. Cell invasion through the Matrigel after 24 hours’ incubation was detected by H&E staining and quantitated. (D and E) Matrigel invasion assay was performed after resuspending MDA-MB231 cells in the conditioned media collected from pcDNA3.1-Neo–, TβRIII-, and sTβRIII-transfected COS-7 cells. Data are mean ± SEM, n = 3 in triplicate. **P < 0.01. (F) Detection of sTβRIII in media of MDA-MB231–TβRIII and 4T1-TβRIII cells by [125I]TGF-β1–binding crosslinking followed by immunoprecipitation.