Neither ovariectomy nor progestin treatment prevents endometrial neoplasia in pten+/- mice.
OBJECTIVE
Hormonal therapy for type I (endometrioid) endometrial carcinoma is employed as both a conservative treatment option and for advanced or recurrent disease, but outcome is often poor. Our objective was to test whether ovariectomy, or ovariectomy followed by progestin treatment prevents the development of endometrial lesions in the pten+/- mouse model of endometrial cancer.


METHODS
pten+/- mice underwent ovariectomy or sham surgery at 6 or 12 weeks of age. Groups of mice were sacrificed at 24, 30 or 40 weeks. Different cohorts of pten+/- mice were ovariectomized at 6 or 12 weeks of age, followed by medroxyprogesterone acetate (MPA) treatment at low or high-dose (25 or 200 mg total dose, respectively) over 21 days, beginning at 30 weeks of age. Uteri from all mice were examined by routine histology and immunohistochemistry.


RESULTS
Without MPA treatment, 16 of 18 ovariectomized animals developed endometrial neoplasms (atypical hyperplasia or adenocarcinoma), as did all 9 sham surgery mice. Immunophenotypes for all tumors were consistent with activation of the phosphoinositidyl-3-kinase (PI3K) pathway, showing staining for phosphorylated PKB/Akt, phosphorylated S6 ribosomal protein and phosphorylated GSK3alpha/beta. All 10 mice treated with either low or high-dose MPA developed endometrial tumors, again with persistent activation of the PI3K signaling pathway.


CONCLUSIONS
Development of endometrial neoplasms and constitutive activation of the PI3K pathway in pten+/- mice is not affected by hormonal ablation or by progestin treatment. Loss of PTEN expression is common during human endometrial cancer development, and this may render lesions resistant to the effects of hormonal manipulation leading to treatment failure.
Fyles
Anthony
A
Department of Radiation Oncology, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada. anthony.fyles@rmp.uhn.on.ca
Wood
Geoffrey
G
Li
Ming
M
Manoukian
Armen S
AS
Gowing
Katrina
K
Khokha
Rama
R
Chapman
William
W
Tsao
Ming-Sound
MS
D000818:Animals; D004195:Disease Models, Animal; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D008297:Male; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D051059:PTEN Phosphohydrolase / Q000235:genetics*
D017258:Medroxyprogesterone Acetate; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse