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Transforming growth factor beta (TGF-beta) reverses phorbol diester resistance of a breast adenocarcinoma (MCF-7)
M Guerrin1, J M Darbon, N Guilbaud
1Laboratoire de Pharmacologie et Toxicologie Fondamentales, CNRS, Toulouse, France.
Abstract:
We investigated the effects of TGF-beta on a MCF-7 subline (MCF-7:RPh-4) which is resistant to phorbol diesters with respect to growth inhibition and estrogen receptor content modulation. This biological unresponsiveness of MCF-7:RPh-4 cells to phorbol esters seems to be unrelated to activation of protein kinase C. In the presence of 80 nM PMA (12-O-tetradecanoylphorbol-13-acetate), TGF-beta induced a dose-dependent inhibition of MCF-7:RPh-4 cell proliferation. MCF-7:RPh-4 cells grown in PMA-free medium for at least 28 days remained insensitive to PMA but lost sensitivity to TGF-beta. Under these conditions, addition of 80 nM PMA restored sensitivity to TGF-beta. In the presence of a fixed concentration of TGF-beta, the dose-dependent inhibition of proliferation and the decrease in estrogen receptor content induced by PMA were comparable to those observed in PMA-treated parental MCF-7 cells. These observations indicate that TGF-beta reverses PMA resistance in MCF-7:RPh-4 cells. In addition, TGF-beta does not modify the basal or PMA-stimulated phosphorylation of Mr 28,000 endogenous protein. These results suggest that TGF-beta interferes with the protein kinase C pathway independently of enzyme activation.
Insights
Transforming growth factor-beta (TGF-beta) can reverse phorbol ester resistance in MCF-7:RPh-4 breast cancer cells. This suggests TGF-beta interferes with the protein kinase C pathway independently of enzyme activation.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- MCF-7:RPh-4 cells exhibit resistance to phorbol diesters (phorbol esters) regarding growth inhibition and estrogen receptor modulation.
- This unresponsiveness to phorbol esters in MCF-7:RPh-4 cells appears independent of protein kinase C activation.
Purpose of the Study:
- To investigate the effects of TGF-beta on MCF-7:RPh-4 cells, specifically their resistance to phorbol esters.
- To determine if TGF-beta can overcome phorbol ester resistance and modulate estrogen receptor content.
Main Methods:
- Treatment of MCF-7:RPh-4 cells with TGF-beta and 12-O-tetradecanoylphorbol-13-acetate (PMA).
- Assessment of cell proliferation, estrogen receptor content, and protein phosphorylation.
- Evaluation of TGF-beta sensitivity restoration by PMA.
Main Results:
- TGF-beta induced dose-dependent inhibition of MCF-7:RPh-4 cell proliferation in the presence of PMA.
- Cells grown without PMA lost TGF-beta sensitivity, which was restored by PMA addition.
- TGF-beta reversed PMA resistance, mimicking effects on parental MCF-7 cells regarding proliferation inhibition and estrogen receptor decrease.
- TGF-beta did not alter basal or PMA-stimulated phosphorylation of a Mr 28,000 protein.
Conclusions:
- TGF-beta effectively reverses phorbol ester resistance in MCF-7:RPh-4 cells.
- TGF-beta appears to interact with the protein kinase C pathway upstream of enzyme activation.