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Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases
Rebecca S. Muraoka, … , Victor Koteliansky, Carlos L. Arteaga
Rebecca S. Muraoka, … , Victor Koteliansky, Carlos L. Arteaga
Published June 15, 2002
Citation Information: J Clin Invest. 2002;109(12):1551-1559. https://doi.org/10.1172/JCI15234.
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Article Development Article has an altmetric score of 15

Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases

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Abstract

TGF-βs are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-β interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-β type II receptor fusion protein (Fc:TβRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TβRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TβRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TβRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TβRII. Therefore, blockade of TGF-β signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.

Authors

Rebecca S. Muraoka, Nancy Dumont, Christoph A. Ritter, Teresa C. Dugger, Dana M. Brantley, Jin Chen, Evangeline Easterly, L. Renee Roebuck, Sarah Ryan, Philip J. Gotwals, Victor Koteliansky, Carlos L. Arteaga

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Figure 1

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Tumor morphology, rate of apoptosis, and Akt signaling are altered by tr...
Tumor morphology, rate of apoptosis, and Akt signaling are altered by treatment with Fc:TβRII. (a) MMTV/PyV mT mice treated with Fc:TβRII or normal mouse IgG were examined twice weekly from 21 to 110 days of age. The initial observation of tumor onset is represented. (b) Histologic sections of tumors from 35- or 70-day-old transgenic or wild-type mice. Arrowheads indicate dilated ducts filled with secretory products. (c) TUNEL analysis (panels 1–4) of tumors harvested from 35- or 70-day-old mice treated with Fc:TβRII or IgG. n = 6 per condition. Quantification of percentage of apoptotic nuclei (bottom right corner of each panel) was calculated using the following equation: (number of TUNEL-positive nuclei in ×400 field) / (number of total nuclei in ×400 field). BrdU incorporation analysis (panels 5–8) of tumors harvested from 70-day-old MMTV/PyV mT or wild-type mice. Arrowheads in panels 7 and 8 indicate BrdU-positive nuclei. Quantification of percentage of BrdU-positive nuclei (bottom right corner of each panel) was calculated using the following equation: (number of BrdU-positive nuclei in ×400 field) / (number of total nuclei in ×400 field). *P = 0.15. Scale bars = 25 μm. (d) Tumor extracts harvested from 110-day-old transgenic mice were subjected to Western blot analysis using Ab’s against the mT Ag, Shc, p85, Akt, p-Akt, FKHRL1, and p-FKHRL. (e) PMTCs were incubated with or without 20 nM Fc:TβRII for 6 hours and stained with a FKHRL1 Ab followed by staining with Cy3-conjugated anti-rabbit Ab. Nuclei were counterstained with DAPI.

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

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