Molecular Human Reproduction, Vol 3, 1019-1027, Copyright © 1997 by Oxford University Press
D Hochner-Celnikier, C Greenfield, Z Finci-Yeheskel, A Milwidsky, A Gutman, D Goldman-Wohl, S Yagel and M Mayer
To elucidate potential mechanisms involved in the increased incidence of
endometrial carcinomas in tamoxifen-treated patients, we examined the
in-vitro effects of tamoxifen on endometrial cancer cells. The effects of
tamoxifen, alone and in combination with oestradiol, on cell proliferation,
plasminogen activator (PA) activity, glycogen synthase and phosphorylase
activities, p53 protein concentration, and collagenase expression were
assessed in two human adenocarcinoma cell lines. These lines were the
oestrogen receptor-positive (Ishikawa) cells, representing 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
combination significantly enhanced cellular proliferation of Ishikawa but
not of HEC-1A cells. Both lines produced appreciable PA activity, most of
which was of the urokinase type. Tamoxifen and oestradiol stimulated this
activity in Ishikawa cells but not in HEC-1A cells. The effect of
oestradiol was dose-dependent in a linear fashion, while tamoxifen 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 of 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 phosphorylase 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 activity in either Ishikawa or HEC-1A
cells. The present findings imply that tamoxifen produces
oestrogen-agonistic effects on cell proliferation and PA activity, and
oestrogen antagonistic effects on glycogen synthase and glycogen
phosphorylase activities, but fails to regulate p53 and gelatinase
expression. The tamoxifen-responsive systems were only observed in
oestrogen-responsive adenocarcinoma cells. Thus, only certain potential
oncogenic effects of tamoxifen can be simulated in vitro, and when present,
these effects are enhanced in the presence of oestradiol.
JOURNAL ARTICLE
Tamoxifen exerts oestrogen-agonistic effects on proliferation and plasminogen activation, but not on gelatinase activity, glycogen metabolism and p53 protein expression, in cultures of oestrogen- responsive human endometrial adenocarcinoma cells
Department of Obstetrics and Gynecology, Hadassah University Hospital, Jerusalem, Israel.
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