Abstract
The transforming growth factor-beta (TGF-beta) signaling pathway plays dual roles in epithelial cell tumorigenesis. 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 (TbetaRIII) in tumorigenesis is less defined. To examine the role of TbetaRIII in breast cancer cells, we stably expressed short hairpin RNAs specific to TbetaRIII 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 TbetaRIII 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-kappaB (NF-kappaB) 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 TbetaRIII-deficient cells to invade Matrigel and decreased their basal level of apoptosis. These data indicate that TbetaRIII 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-kappaB activity.
Highlights
Transforming growth factor-h (TGF-h) belongs to a family of growth factors known to regulate cell growth and motility [1]
High expression of TBRIII correlates with breast cancer cell invasiveness
Our data indicate that high ThRIII expression correlates with the ability to form invasive structures in Matrigel and suggest that ThRIII correlates with metastatic properties of breast cancer cells
Summary
Transforming growth factor-h (TGF-h) belongs to a family of growth factors known to regulate cell growth and motility [1]. TGF-h1 and TGF-h3 can bind with high affinity to the TGF-h type II receptor (ThRII), which results in the recruitment of the type I receptor (ThRI). The constitutively active type II serine-threonine kinase phosphorylates and activates the type I receptor kinase, which results in recruitment and activation of Smads 2 and 3. Smad 4 is able to bind to activated Smad 2/3, and the entire complex translocates to the nucleus to activate downstream target genes [1, 2]. The type II receptor binds with low affinity to TGF-h2. The type III receptor (ThRIII) or betaglycan binds with
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