Expression of transforming growth factor beta (TGF beta) type III receptor restores autocrine TGF beta(1) activity in human breast cancer MCF-7 cells

While transforming growth factor beta (TGF beta) type III receptor (RIII) is known to increase TGF beta(1) binding to its type nr receptor (RII), the significance of this phenomenon is not known. We used human breast cancer MCF-7 cells to study the role of RIII in regulating autocrine TGF beta(1), activity because they express very little RIII and no detectable autocrine TGF beta activity. A tetracycline-repressible RIII expression vector was stably transfected into this cell line. Expression of RIII increased TGF beta(1) binding to TGF beta type I receptor (RI) as well as RII. Treatment with tetracycline suppressed RIII expression and abolished TGF beta(1) binding to RI and RII. Growth of RIII-transfected cells was reduced by 40% when plated at low density on plastic. This reduction was reversed by tetracycline treatment and was partially reversed by treatment with a TGF beta(1) neutralizing antibody. The activity of a TGF beta-responsive promoter construct when transiently transfected was more than S-fold higher in the RIII-transfected cells than in the control cells. Treating the cells with tetracycline or the TGF beta(1) neutralizing antibody also significantly attenuated the increased promoter activity. These results suggest that expression of RIII restored autocrine TGF beta(1) activity in MCF-7 cells. The RIII-transfected cells mere also much less clonogenic in soft agarose than the control cells indicating a reversion of progression. Thus, RIII may be essential for an optimal level of the autocrine TGF beta activity in some cells, especially in the transformed cells with reduced RII expression.