A kinase-defective transforming growth factor-ß receptor type II is a dominant-negative regulator for human breast carcinoma MCF-7 cells

The role of transforming growth factor (TGF)-ß type II receptor (TßRII) in TGF-ß resistance and tumor progression is now well recognized. To test the effects of TßRII loss in determining malignancy, we transfected a TßRII-expressing, TGF-ß-sensitive, MCF-7 cell strain (ME24) with a tetracycline-repressible truncated TßRII (kdTßRII) construct lacking the cytoplasmic domain of the receptor. Transfection of kdTßRII into parental ME24 cells (designated ME24t6 after transfection) resulted in high expression levels of kdTßRII mRNA and cell surface protein which were reversible by tetracycline treatment. ME24t6 cells did not respond to exogenous TGF-ß1 as measured by inhibition of proliferation or fibronectin (FN) induction, indicating that the truncated TßRII acted as a dominant-negative inhibitor of both the growth inhibitory and extracellular matrix (ECM) stimulatory TGF-ß effects. Furthermore, inhibition of kdTßRII expression by tetracycline treatment led to TGF-ß1-mediated cell growth arrest in the G1 phase of cell cycle and to the accumulation of the hypophosphorylated form of retinoblastoma (Rb) protein. However, compared to parental ME24 cells, transfectants failed to show increased tumorigenicity, indicating that loss of TßRII itself is not sufficient to account for differences in the malignant properties of TßRII-expressing and non-expressing MCF-7 cell strains.