ENHANCED C-JUN ACTIVITY ALTERS RESPONSIVENESS TO MEDROXYPROGESTERONE ACETATE IN ISHIKAWA HUMAN ENDOMETRIAL CARCINOMA-CELLS

The involvement of altered c-jun activity in medroxyprogesterone acetate (MPA)-induced growth responses in human endometrial carcinoma cells is examined in this paper. Under conditions of (MPA)-induced growth inhibition, c-jun mRNA and protein levels are decreased in Ishikawa cells. This decrease is accompanied by an overall decrease in endogenous AP-1 activity in these cells. Only a transient decrease in c-jun mRNA level without any effect on endogenous AP-1 activity is seen in HEC-50 human endometrial carcinoma cells after MPA treatment. Increased expression and activity of c-jun was achieved in Ishikawa cells by transient transfection of Rous sarcoma virus (RSV)-c-jun alone or RSV-c-jun plus AP-1 binding sites (5x-4-beta-phorbol 12-myristate 13-acetate response element-thymidine kinase-chloramphenicol acetyltransferase), respectively. These treatments were accompanied by an increase in cell numbers due to MPA treatment in Ishikawa cells. In contrast, MPA treatment of mock-transfected, RSV-jun-B-transfected, or 5x-4 beta-phorbol 12-myristate 13-acetate response element-thymidine kinase-chloramphenicol acetyltransferase alone transfected Ishikawa cells resulted in the expected decrease in cell numbers. The data presented in this paper are consistent with the hypothesis that altered c-jun activity in a target cell can alter proliferative responsiveness to MPA and suggest that such a mechanism may be associated with resistance to hormonal manipulative therapies used in the treatment of both human breast and endometrial cancer.