A KINASE-DEFECTIVE TRANSFORMING-GROWTH-FACTOR-BETA RECEPTOR-TYPE-II IS A DOMINANT-NEGATIVE REGULATOR FOR HUMAN BREAST-CARCINOMA MCF-7 CELLS

The role of transforming growth factor (TGF)-beta type II receptor (T beta RII) in TGF-beta resistance and tumor progression is now well rec ognized. To test the effects of T beta RII loss in determining maligna ncy, we transfected a T beta RII-expressing, TGF-beta-sensitive, MCF-7 cell strain (ME24) with a tetracycline-repressible truncated T beta R II (kdT beta RII) construct lacking the cytoplasmic domain of the rece ptor. Transfection of kdT beta RII into parental ME24 cells (designate d ME24t6 after transfection) resulted in high expression levels of kdT beta RII mRNA and cell surface protein which were reversible by tetra cycline treatment. ME24t6 cells did not respond to exogenous TGF-beta 1 as measured by inhibition of proliferation or fibronectin (FN) induc tion, indicating that the truncated TORII acted as a dominant-negative inhibitor of both the growth inhibitory and extracellular matrix (ECM ) stimulatory TGF-B effects. Furthermore, inhibition of kdT beta RII e xpression by tetracycline treatment led to TGF-beta 1-mediated cell gr owth arrest in the G1 phase of cell cycle and to the accumulation of t he hypophosphorylated form of retinoblastoma (Rb) protein. However, co mpared to parental ME24 cells, transfectants failed to show increased tumorigenicity, indicating that loss of T beta RII itself is not suffi cient to account for differences in the malignant properties of T beta RII-expressing and non-expressing MCF-7 cell strains.