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

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 5

TβRIII decreased tumor cell invasiveness and metastasis in vivo.

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TβRIII decreased tumor cell invasiveness and metastasis in vivo. Represe...
Representative H&E staining (original magnification, ×10) of (A and B) primary tumors from mice implanted with 4T1-Neo cells exhibiting local invasion (red arrows) of tumor cells into the adjacent normal mammary tissue (A) and skin (B); (C) a representative primary tumor from mice implanted with 4T1-TβRIII cells demonstrating the absence of local invasion, as indicated by the clear margin between the tumor and the adjacent normal mammary tissue (yellow arrow); (D) a recurring tumor in a mouse at the primary injection site of 4T1-Neo cells exhibiting internal bleeding due to invasion of tumor cells into the blood vessels; (E) a metastatic tumor (black arrow) adjacent to the pancreas (green arrowhead) found on the mesentery of a mouse implanted with 4T1-Neo cells; (F) a significantly enlarged paratracheal lymph node adjacent to the trachea (blue arrowhead) containing metastatic tumor cells (black arrow) in a mouse with 4T1-Neo cells, indicating the presence of lymphatic metastasis; (G) multiple large metastatic tumor nodules (black arrows) in the lung of a mouse implanted with 4T1-Neo cells; and (H and I) representative lung metastases in mice implanted with 4T1-TβRIII cells (black arrows).