Reconstitution of TGF-β sensitivity in the VACO-411 human colon carcinoma line by somatic cell fusion with MCF-7

We characterized the mechanism of transforming growth factor beta (TGF-β) resistance in the VACO-411 human colon carcinoma line. VACO-411 is unique for several reasons, including having a novel mutator phenotype and wild-type p53. Like many colon tumors, VACO-411 is not growth inhibited by TGF-β. However, VACO-411 represents a subset of colon tumors that are resistant to TGF-β-mediated growth inhibition, despite the expression of functional TGF-β receptors. VACO-411 expresses cell surface TGF-β receptor types I and II, and the coding regions of these receptors are wild type. To further characterize the nature of the VACO-411 defect, we fused VACO-411 with the human breast carcinoma line MCF-7. MCF-7 is also resistant to TGF-β-mediated growth inhibition. However, unlike VACO-411, MCF-7 lacks cell surface expression of TGF-β receptor type II, but does contain an intact postreceptor signaling pathway, as shown by regeneration of TGF-β sensitivity following wild-type TGF-β receptor type II transfection. In contrast to parental VACO-411 and MCF-7, the morphologically distinct cell hybrids were growth inhibited by TGF-β. Therefore, the TGF-β defect in VACO-411 is a postreceptor, loss-of-function mutation which can be genetically complemented. The data suggest that the VACO-411 defect in TGF-β signaling will be able to be further complemented by microcell-mediated chromosome transfer.