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Knockdown of the Transforming Growth Factor-β Type III Receptor Impairs Motility and Invasion of Metastatic Cancer Cells

Departments of ¹ Cancer Biology, ² Medicine, and ³ Pharmacology, and ⁴ Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; and ⁵ Department of Pathology, University of California at San Francisco, San Francisco, California

Requests for reprints: Carlos L. Arteaga, Division of Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN 37232-6307. Phone: 615-936-3524; Fax: 615-936-1790; E-mail: carlos.arteaga{at}vanderbilt.edu.

Key Words: TGF-β • epithelial-to-mesenchymal transition • metastasis • breast cancer

The transforming growth factor-β (TGF-β) signaling pathway plays dual roles in epithelial cell tumorigenesis. TGF-β is initially growth inhibitory, but as tumorigenesis progresses, TGF-β becomes prometastatic. Although the role of the types I and II TGF-β receptors is fairly well established, the role of the ubiquitously expressed TGF-β type III receptor (TβRIII) in tumorigenesis is less defined. To examine the role of TβRIII in breast cancer cells, we stably expressed short hairpin RNAs specific to TβRIII in MDA-231 human breast cancer cells and mouse mammary carcinoma cells expressing the polyomavirus middle T oncogene (PMTLuc). MDA-231 and PMTLuc cells with down-regulated TβRIII expression (231-kd; PMTLuc-kd) exhibited decreased growth rate, motility, and invasion into Matrigel, as well as an increase in apoptosis, compared with control cells. MDA-231 xenografts established in nude mice metastasized, whereas tumors made by 231-kd cells did not. Nuclear factor-B (NF-B) activity, which is known to regulate cell growth and motility, was lower in the MDA-231 and PMTLuc knockdown cells compared with control cells. Transfection of an expression vector encoding constitutively active IKK2 into the 231-kd cells restored the ability of TβRIII-deficient cells to invade Matrigel and decreased their basal level of apoptosis. These data indicate that TβRIII differentially regulates cell growth, motility, and invasion in tumorigenic MDA-231 and PMTLuc cells and that these growth changes occur through the modulation of NF-B activity. [Cancer Res 2008;68(18):7304–12]

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