Additive effect of mifepristone and tamoxifen on apoptotic pathways in MCF-7 human breast cancer cells

MCF-7 cells growing in culture were used to study the mechanism of the anti proliferative activity of the antiprogestin mifepristone, as compared with the antiestrogen 4-hydroxytamoxifen or the combination of bath. These stero id antagonists induced a significant time- and dose-dependent cell growth i nhibition (cytotoxicity). This inhibition of cell survival was associated w ith a significant increase in DNA fragmentation (apoptosis), downregulation of bcl(2), and induction of TGF beta(1) protein. Abrogation of the mifepri stone- and/or 4-hydroxytamoxifen-induced cytotoxicity by TGF beta(1) neutra lizing antibody confirms the correlation between induction of active TGF be ta(1) and subsequent cell death. The effect of a combination of mifepriston e and 4-hydroxytamoxifen on cell growth inhibition, on the increase in DNA fragmentation, bcl(2) downregulation, and induction of TGF beta(1) protein was additive and significantly different (P < 0.05) from the effect of mono therapy. A translocation of protein kinase C (PKC) activity from the solubl e to the particulate and/or nuclear fraction appeared to be also additive i n cells treated with a combination of both 4-hydroxptamoxifen and mifeprist one. These results suggest that the mechanism of the additive antiprolifera tive activity of mifepristone and tamoxifen could be explained at least in part by an additive induction of apoptosis in both estrogen and progesteron e receptor positive MCF-7 breast cancer cells. A bcl(2) downregulation, the PKC transduction pathway, and TGF beta(1) expression seem to be involved i n this additive mechanism of action. Our data further suggest that a combin ation of an antiprogestin with tamoxifen may be more effective than tamoxif en monotherapy in the management of human breast cancer.