EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA TYPE-II RECEPTOR LEADS TO REDUCED MALIGNANCY IN HUMAN BREAST-CANCER MCF-7 CELLS

The role of transforming growth factor (TGF) beta type II receptor in reversing the malignant phenotype of human breast cancer MCF-7 cells w as examined. MCF-7 cells were insensitive to TGF beta(1) and expressed undetectable levels of cell surface TGF beta type I receptor (RI) and type II receptor (RII) by cross-linking with I-125-TGF beta(1). Stabl e transfection of a RII expression vector yielded 3 transfectants with varying levels of exogenous RII mRNA and protein levels. Expression o f RII also increased TGF beta(1) binding to RI in all 3 clones. Prolif eration of RII-positive clones was inhibited by exogenous TGF beta(1) in a dose-dependent manner, whereas the control clones remained TGF be ta-insensitive. The RII transfectants were growth arrested in monolaye r culture at saturation densities which were 41-66% of that of the Neo controls. They also showed reduced clonogenicity in soft-agarose. Tum origenicity in ovariectomized, estrogen-supplemented nude mice was del ayed in transfectants with low RII levels. Transfectants expressing hi gh levels of RII showed a large reduction in tumorigenicity as well as a longer delay in tumor formation. Tumor growth was associated with l oss of exogenous RII expression in transfectants. The results indicate that when systems for TGF beta signal transduction are intact, recons titution of the TGF beta receptor system can lead to reversion of mali gnancy in cells lacking RII.