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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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Research Article Oncology

The type III TGF-β receptor suppresses breast cancer progression

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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 1

Loss of TβRIII mRNA expression during mammary carcinogenesis.

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Loss of TβRIII mRNA expression during mammary carcinogenesis.
(A) TβRIII...
(A) TβRIII mRNA levels were detected by hybridizing [32P]-labeled human TβRIII cDNA probe to the Clontech Cancer Profiling Array I. The portion of the array containing breast samples is shown, with tumor specimens (T) and matched normal breast tissue (N). Asterisks indicate metastatic specimens corresponding to the normal and tumor samples spotted on the immediate left. (B) Quantitative data were obtained by analyzing the array with NIH ImageJ software, summarized as the ratio relative to normal breast, and expressed as mean ± SEM. (C) Quantitative data from matched normal, primary breast tumor, and metastatic breast tumor tissue expressed as mean ± SEM. ***P < 0.0001, ANOVA.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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