Knockdown of the transforming growth factor-β type III receptor impairs motility and invasion of metastatic cancer cells

The transforming growth factor-beta (TGF-beta) signaling pathway plays dual roles in epithelial cell turnorigenesis. TGF-beta is initially growth inhibitory, but as tumorigenesis progresses, TGF-beta becomes prometastatic. Although the role of the types I and II TGF-beta receptors is fairly well established, the role of the ubiquitously expressed TGF-beta type III receptor (T beta RIII) in tumorigenesis is less defined. To examine the role of T beta RIII in breast cancer cells, we stably expressed short hairpin RNAs specific to T beta RIII 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 T beta RIII 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-kappa B (NF-kappa 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 T beta RIII-deficient cells to invade Matrigel and decreased their basal level of apoptosis. These data indicate that T beta RIII 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-kappa B activity.