Reduced progression of endometrial hyperplasia with oral mTOR inhibition in the Pten heterozygote murine model.
OBJECTIVE
Phosphatase and tensin homolog (PTEN) mutations are associated with human endometrial cancers, and PTEN heterozygote(+/-) mice have a high rate of endometrial neoplasia. The objective of this study was to evaluate an oral mTOR inhibitor (mTOR-I) on the reduction of endometrial hyperplasia in an animal model.


METHODS
Three groups of 10 female mice were treated from age 20-26 weeks: group A, Pten wild type with mTOR-I; group B, Pten+/- with placebo; and group C, Pten +/- with mTOR-I. Rates of hyperplasia and markers of proliferation and apoptosis were evaluated.


RESULTS
Higher grade hyperplasia occurred in a significantly greater percentage of the untreated Pten+/- group B (80%; 8/10) compared with groups A (0%; 0/10) and C (20%; 2/10; P < .02). The treated Pten+/- mTOR-I group C also demonstrated significantly increased apoptosis (P < .002) and decreased proliferation index (P < .02) compared with the untreated group B.


CONCLUSIONS
Oral mTOR inhibition decreases the progression of endometrial hyperplasia in the Pten heterozygote murine model through decreased cell proliferation and increased apoptosis.
Milam
Michael R
MR
Department of Gynecologic Oncology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Celestino
Joseph
J
Wu
Weiguo
W
Broaddus
Russell R
RR
Schmeler
Kathleen M
KM
Slomovitz
Brian M
BM
Soliman
Pamela T
PT
Gershenson
David M
DM
Wang
Hong
H
Ellenson
Lora H
LH
Lu
Karen H
KH
D000284:Administration, Oral; D000818:Animals; D018450:Disease Progression; D004714:Endometrial Hyperplasia / Q000188:drug therapy* / Q000235:genetics*; D000068338:Everolimus; D005260:Female; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011494:Protein Kinases / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases
D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020123:Sirolimus