Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium.
Epithelial-specific activation of the PI3-kinase pathway is the most common genetic alteration in type I endometrial cancer. In the majority of these tumors, PTEN expression is lost in the epithelium but maintained in tumor stroma. Currently reported PTEN knockout mouse models initiate type I endometrial cancer concomitant with loss of PTEN in both uterine epithelium and stroma. Consequently, the biologic outcome of selectively activating the PI3-kinase pathway in the endometrial epithelium remains unknown. To address this question, we established a malleable in vivo endometrial regeneration system from dissociated murine uterine epithelium and stroma. Regenerated endometrial glands responded to pharmacologic variations in hormonal milieu similar to the native endometrium. Cell-autonomous activation of the PI3-kinase pathway via biallelic loss of PTEN or activation of AKT in adult uterine epithelia in this model was sufficient to initiate endometrial carcinoma. AKT-initiated tumors were serially transplantable, demonstrating permanent genetic changes in uterine epithelia. Immunohistochemistry confirmed loss of PTEN or activation of AKT in regenerated hyperplastic glands that were surrounded by wild-type stroma. We demonstrate that cell-autonomous activation of the PI3-kinase pathway is sufficient for the initiation of endometrial carcinoma in naive adult uterine epithelia. This in vivo model provides an ideal platform for testing the response of endometrial carcinoma to targeted therapy against this common genetic alteration.
Memarzadeh
Sanaz
S
Department of Obstetrics and Gynecology, The David Geffen School of Medicine, Los Angeles, CA 90095, USA. smemarzadeh@mednet.ucla.edu
Zong
Yang
Y
Janzen
Deanna M
DM
Goldstein
Andrew S
AS
Cheng
Donghui
D
Kurita
Takeshi
T
Schafenacker
Amanda M
AM
Huang
Jiaoti
J
Witte
Owen N
ON
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000328:Adult; D000818:Animals; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000473:pathology; D004717:Endometrium / Q000033:anatomy & histology / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse