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-κB (NF-κB) 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-κB activity.
ASJC Scopus subject areas
- Cancer Research