Effects of metformin on mammalian target of rapamycin in a mouse model of endometrial hyperplasia.
OBJECTIVE
The effects of metformin on S6K1, which is a crucial effector of mTOR signaling, and on endometrium were studied in a mouse model of endometrial hyperplasia induced by unopposed estradiol or tamoxifen.


METHODS
Forty-eight oophorectomized Balb/c mice were randomly assigned to receive saline, tamoxifen citrate (4 mg/kg), 17-beta estradiol hemihydrate (4 mg/kg), metformin (50 mg/kg), tamoxifen citrate (4 mg/kg) with metformin (50 mg/kg), or estradiol (4 mg/kg) with metformin (50 mg/kg) for 3 days. Histological markers of uterotrophy, including luminal epithelial cell height and density of endometrial glands were quantified for each slide. Immunohistochemical expression of PCNA and S6K1 was evaluated. H-score was used for S6K1 expression. Statistical analysis was performed using Student's t-test for comparison of two continous variables and one-way ANOVA for comparison of multiple variables.


RESULTS
Mice treated either with tamoxifen or estradiol had significantly increased density of endometrial glands and epithelial heights compared to vehicle-only or metformin-only group (p<0.001). Addition of metformin to tamoxifen or estradiol treated mice significantly decreased the density of endometrial glands and epithelial cell heights (p<0.05). Addition of metformin to tamoxifen significantly decreased the H-score of S6K1 (p<0.05) and the immunohistochemical expression of PCNA (p<0.05) in uterine lining epithelium, glandular and stromal cells. Addition of metformin to estradiol significantly decreased the H-score of S6K1 (p<0.05) and the immunohistochemical expression of PCNA (p<0.05) in uterine lining epithelium, glandular and stromal cells.


CONCLUSIONS
Metformin seems to have possible antiproliferative effects on the endometrium of estradiol or tamoxifen treated mice via inhibiting the mTOR mediated S6K1 activation.
Erdemoglu
Evrim
E
Department of Obstetrics and Gynecology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey. erdemoglu@med.sdu.edu.tr
Güney
Mehmet
M
Giray
Seren Gülşen
SG
Take
Gülnur
G
Mungan
Tamer
T
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004714:Endometrial Hyperplasia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000187:drug effects; D004958:Estradiol; D005260:Female; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000187:drug effects*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen
D002352:Carrier Proteins; D013629:Tamoxifen; D004958:Estradiol; D008687:Metformin; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases