TAMOXIFEN EXERTS ESTROGEN-AGONISTIC EFFECTS ON PROLIFERATION AND PLASMINOGEN ACTIVATION, BUT NOT ON GELATINASE ACTIVITY, GLYCOGEN-METABOLISM AND P53 PROTEIN EXPRESSION, IN CULTURES OF ESTROGEN-RESPONSIVE HUMANENDOMETRIAL ADENOCARCINOMA CELLS

To elucidate potential mechanisms involved in the increased incidence of endometrial carcinomas in tamoxifen-treated patients, we examined t he in-vitro effects of tamoxifen on endometrial cancer cells. The effe cts of tamoxifen, alone and in combination with oestradiol, on cell pr oliferation, plasminogen activator (PA) activity, glycogen synthase an d phosphorylase activities, p53 protein concentration, and collagenase expression were assessed in two human adenocarcinoma cell lines. Thes e lines were the oestrogen receptor-positive (Ishikawa) cells, represe nting a well-differentiated endometrial adenocarcinoma, and oestrogen receptor-negative (HEC-1A) cells, derived from a poorly differentiated endometrial adenocarcinoma. Tamoxifen or oestradiol alone and their c ombination significantly enhanced cellular proliferation of Ishikawa b ut not of HEC-1A cells. Both lines produced appreciable PA activity, m ost of which was of the urokinase type. Tamoxifen and oestradiol stimu lated this activity in Ishikawa cells but not in HEC-1A cells. The eff ect of oestradiol was dose-dependent in a linear fashion, while tamoxi fen produced a stimulation peaking at 10(-8) M and declining at higher concentrations. Tamoxifen in combination with oestradiol exhibited a synergistic effect on proliferation and on PA activity. The response o f PA extended beyond the increase in proliferation, leading to higher specific activity of PA in the tamoxifen-treated cultures. In Ishikawa cells, oestradiol also increased glycogen synthase and glycogen phosp horylase activities, while tamoxifen markedly suppressed these enzymes . Oestradiol, tamoxifen, and their combination had no apparent effect on the expression of protein p53 in Ishikawa cells, or on gelatinase a ctivity in either Ishikawa or HEC-1A cells. The present findings imply that tamoxifen produces oestrogen-agonistic effects on cell prolifera tion and PA activity, and oestrogen antagonistic effects on glycogen s ynthase and glycogen phosphorylase activities, but fails to regulate p 53 and gelatinase expression. The tamoxifen-responsive systems were on ly observed in oestrogen-responsive adenocarcinoma cells. Thus, only c ertain potential oncogenic effects of tamoxifen can be simulated in vi tro, and when present, these effects are enhanced in the presence of o estradiol.