Expression of transforming growth factor-β receptor type II and tumorigenicity in human breast adenocarcinoma MCF-7 cells

To analyze transforming growth factor-β (TGF-β) response during MCF-7 cell progression, early passage (MCF-7E, <200 passage) and late passage (MCF- 7L, > 500 passage) cells were compared. MCF-7E cells showed an IC₅₀ of ~ 10 ng/ml of TGF-β1, whereas MCF-7L cells were insensitive, MCF-7E cells contained approximately threefold higher levels of TGF-β receptor type II (TβRII) mRNA than MCF-7L, but their TβRI levels were similar, MCF-7E parental cells showed higher TβRI promoter activity than MCF-7L cells, which could be attributed to changes in Sp1 nuclear protein levels. Receptor cross- linking studies indicated that the cell surface receptor levels parallel mRNA levels in both cell lines. Limiting dilution clones MCF-7E cells were established to determine the heterogenecity of TβRII expression in this cell line, and they showed varying degrees of TβRII expression. Fibronectin was induced at higher levels in cells expressing higher TβRII levels. All three TGF-β isoforms were detected in limiting dilution clones and parental cells, but TGF-β1 was more abundant relative to TGF-β2 or 3, and no correlation between TGF-β isoform profile with TGF-β sensitivity was found. MCF-7l cells were tumorigenic and formed xenografts rapidly and progressively, whereas MCF-7E parental and limiting dilution clonal cells showed transient tumor formation followed by regression. These results indicate that decrease TβRII transcription in breast cancer cells leads to loss of TβRII expression resulting in cellular resistance to TGF-β which contributes to escape from negative growth regulation and tumor progression.