Effects of tamoxifen and raloxifene on normal human endometrial cells in an organotypic in vitro model.
The selective estrogen receptor modulator tamoxifen is widely used in breast cancer therapy though its use is associated with an elevated risk of endometrial carcinoma. An organotypic culture model was employed here to examine the effects of tamoxifen and raloxifene, a related compound with no known adverse uterine effects, on epithelial cells of the premenopausal human endometrium. Changes in the expression levels of the proliferation marker Ki67, and estrogen and progesterone receptors were evaluated. No change in the Ki67 index compared to untreated controls was detected in cultures exposed to tamoxifen or tamoxifen+estradiol. In response to tamoxifen, the level of progesterone receptor-expressing organoids was shown to vary markedly between individual samples, whereas no change in estrogen receptor expression could be demonstrated. A significant decrease in Ki67 expression was observed in raloxifene-exposed cultures. Raloxifene or raloxifene+estradiol had no effect on progesterone receptor expression. The expression of estrogen receptor was markedly inhibited in response to raloxifene or raloxifene+estradiol in all but two samples displaying an intense estrogen receptor labelling. The present observations add to current clinical data on the respective estrogen receptor agonist and antagonist activities of tamoxifen and raloxifene on the human uterus by providing novel insights into the interindividual variation in cellular responses. Our organotypic model may have uses as an alternative to animal experimentation in preclinical screening of the endometrial effects of selective estrogen receptor modulators and may serve as a tool in personalized medicine by identifying patients with an increased risk of developing endometrial pathologies.
Bläuer
Merja
M
Department of Cell Biology, FI-33014, University of Tampere, Finland. merja.blauer@uta.fi
Heinonen
Pentti K
PK
Rovio
Päivi
P
Ylikomi
Timo
T
D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects; D004717:Endometrium / Q000166:cytology* / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D009924:Organ Culture Techniques; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000096:biosynthesis; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*
D047628:Estrogen Receptor alpha; D019394:Ki-67 Antigen; D011980:Receptors, Progesterone; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol