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

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 4

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Fc:TβRII inhibits 4T1 and EMT6 primary tumor size and lung metastases. T...
Fc:TβRII inhibits 4T1 and EMT6 primary tumor size and lung metastases. Tumor cells (0.5 × 105 4T1 or EMT6) were injected into the mammary fat pad of BALB/c mice. Mice were treated twice weekly with Fc:TβRII. (a) After 10 days, primary tumors were resected. Arrows indicate the lymph nodes of the number 4 mammary gland. The average tumor volume (n = 8 per condition), calculated by the formula vol-ume = width2 × length/2, is indicated in the lower right corner. *P = 0.011; **P = 0.05. (b) Lungs were collected at 8 weeks and examined for lung surface metastases. Arrows indicate metastases. The average number of metastases per mouse is shown in the bottom right corner of each panel (n = 8 per condition). *P = 0.026; **P = 0.034.