Expression of transforming growth factor β type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells

The role of transforming growth factor (TGF) β type II receptor in reversing the malignant phenotype of human breast cancer MCF-7 cells was examined. MCF-7 cells were insensitive to TGFβ₁ and expressed undetectable levels of cell surface TGFβ type I receptor (RI) and type II receptor (RII) by cross-linking with ¹²⁵I-TGFβ₁. Stable transfection of a RII expression vector yielded 3 transfectants with varying levels of exogenous RII mRNA and protein levels. Expression of RII also increased TGFβ₁ binding to RI in all 3 clones. Proliferation of RII-positive clones was inhibited by exogenous TGFβ₁ in a dose-dependent manner, whereas the control clones remained TGFβ-insensitive. The RII transfectants were growth arrested in monolayer culture at saturation densities which were 41-66% of that of the Neo controls. They also showed reduced clonogenicity in soft-agarose. Tumorigenicity in ovariectomized, estrogen-supplemented nude mice was delayed in transfectants with low RII levels. Transfectants expressing high levels of RII showed a large reduction in tumorigenicity as well as a longer delay in tumor formation. Tumor growth was associated with loss of exogenous RII expression in transfectants. The results indicate that when systems for TGFβ signal transduction are intact, reconstitution of the TGFβ receptor system can lead to reversion of malignancy in cells lacking RII.