The effects of the selective estrogen receptor modulators, methyl-piperidino-pyrazole (MPP), and raloxifene in normal and cancerous endometrial cell lines and in the murine uterus.
Since estrogens have vital functions in the uterus but might also contribute to endometrial cancer, we sought to determine the in vitro effects of methyl-piperidino-pyrazole (MPP), raloxifene, and beta-estradiol on Ishikawa and RL-95 endometrial cancer, and ovine luminal endometrial (oLE) cell lines and the in vivo effects of these compounds in the rodent uterus. MPP and raloxifene (1 nM) induced significant apoptosis in the endometrial cancer and oLE cell lines compared to beta-estradiol treated and control cells (P <or= 0.0001-0.001). To determine the in vivo uterine effects of these compounds, ovariectomized wild-type (WT) and estrogen receptor-beta knockout (ERbetaKO) mice were treated with 25, 50, 100, or 150 microg of each compound. Although raloxifene caused no significant increase in uterine weight, the presumptive ERalpha antagonist, MPP (25-150 microg) increased uterine weight, and cell proliferation significantly relative to vehicle control in WT and ERbetaKO mice (P <or= 0.001). However, MPP did not increase uterine wet weight as effectively as beta-estradiol (P <or= 0.0001), and administration of either 50 microg of MPP or raloxifene effectively reversed the positive effects of 50 and 100 microg beta-estradiol. Unexpectedly, in view of the in vitro studies, MPP and raloxifene treatment of ovariectomized mice did not induce apoptosis of the luminal epithelial cells but rather these compounds induced apoptosis of the underlying uterine stromal cells. These results demonstrate that MPP and raloxifene can exert apparently contrasting in vitro versus in vivo effects, and that they have mixed agonist/antagonist action on murine uterine ERalpha in vivo.
Davis
Angela M
AM
Biomedical Sciences, University of Missouri, Life Sciences Center, Columbia, 65211, USA.
Ellersieck
Mark R
MR
Grimm
Kristie M
KM
Rosenfeld
Cheryl S
CS