Expression of transforming growth factor β (TGFβ) type III receptor restores autocrine TGFβ₁ activity in human breast cancer MCF-7 cells

While transforming growth factor β (TGFβ) type III receptor (RIII) is known to increase TGFβ₁ binding to its type II 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 TGFβ₁ activity because they express very little RIII and no detectable autocrine TGFβ activity. A tetracycline-repressible RIII expression vector was stably transfected into this cell line. Expression of RIII increased TGFβ₁ binding to TGFβ type I receptor (RI) as well as RII. Treatment with tetracycline suppressed RIII expression and abolished TGFβ₁ 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 TGFβ₁ neutralizing antibody. The activity of a TGFβ₁-responsive promoter construct when transiently transfected was more than 3-fold higher in the RIII-transfected cells than in the control cells. Treating the cells with tetracycline or the TGFβ₁ neutralizing antibody also significantly attenuated the increased promoter activity. These results suggest that expression of RIII restored autocrine TGFβ₁ activity in MCF-7 cells. The RIII-transfected cells were 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 TGFβ activity in some cells, especially in the transformed cells with reduced RII expression.