Using a cell model system established by ectopic expression of a soluble TGFbeta type III receptor (sRIII) containing the whole extracellular domain of the type III receptor in human breast cancer MDA-MB-231 cells, we observed that the expression of sRIII antagonized TGFbeta activity and inhibited both anchorage-dependent and anchorage-independent cell growth. Further studies revealed that sRIII expression induced apoptosis both in vitro and in vivo. Treatment with TGFbeta neutralizing antibodies or a recombinant human sRIII also induced apoptosis in the MDA-MB-231 parental cells, suggesting that the increased apoptosis after sRIII expression was specifically due to antagonization of autocrine TGFbeta signaling. Western blotting showed that sRIII clones had a higher PTEN expression level than the control cells did. Treatment with TGFbeta(1) decreased PTEN and inhibited apoptosis in sRIII cells to a level similar to that in the control cells. sRIII clones also showed a lower level of phosphorylated-Akt than the control cells, consistent with the inhibitory activity of PTEN on Akt activation. Treatment with LY294002, a specific inhibitor of Akt activator, phosphatidylinositol 3-kinase, also induced apoptosis in a dose dependent manner in the control cells. Our results suggest that autocrine TGFbeta signaling is necessary for the growth and survival of MDA-MB-231 cells.