The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten

Abstract

Mutation of the tumor suppressor Pten often leads to tumorigenesis in various organs including the uterus. We previously showed that Pten deletion in the mouse uterus using a Pgr-Cre driver (Ptenf/fPgrCre/+) results in rapid development of endometrial carcinoma (EMC) with full penetration. We also reported that Pten deletion in the stroma and myometrium using Amhr2-Cre failed to initiate EMC. Since the Ptenf/fPgrCre/+ uterine epithelium was primarily affected by tumorigenesis despite its loss in both the epithelium and stroma, we wanted to know if Pten deletion in epithelia alone will induce tumorigenesis. We found that mice with uterine epithelial loss of Pten under a Ltf-iCre driver (Ptenf/f/LtfCre/+) develop uterine complex atypical hyperplasia (CAH), but rarely EMC even at 6 months of age. We observed that Ptenf/fPgrCre/+ uteri exhibit a unique population of cytokeratin 5 (CK5) and transformation related protein 63 (p63)-positive epithelial cells; these cells mark stratified epithelia and squamous differentiation. In contrast, Ptenf/fLtfCre/+ hyperplastic epithelia do not undergo stratification, but extensive epithelial cell apoptosis. This increased apoptosis is associated with elevation of TGFβ levels and activation of downstream effectors, SMAD2/3 in the uterine stroma. Our results suggest that stromal PTEN via TGFβ signaling restrains epithelial cell transformation from hyperplasia to carcinoma. In conclusion, this study, using tissue-specific deletion of Pten, highlights the epithelial-mesenchymal cross-talk in the genesis of endometrial carcinoma.

Reply to Liu et al.: ALK5-mediated tumor suppressor signaling through SMAD2 and SMAD3 in the uterus

“…Our recent publications in PNAS (1,2) describe the phenotypic effects of loss of activin-like kinase 5; transforming growth factor β receptor 1 (ALK5;TGFBR1) or Smad2 and Smad3 in the mouse uterus and are accompanied by a commentary by Li (3). Our conclusions are that this pathway acts as a tumor suppressor pathway, findings that are also supported by a recent paper (4). We appreciate the letter to the editor by Liu et al (5); however, their analysis is performed utilizing data from uterine cancer samples from The Cancer Genome Atlas (TCGA) and should be cautiously interpreted for the following reasons:…”

Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

“…We conclude that Fbxw7/Pten tumors begin as usual-type endometrioid adenocarcinomas, but evolve in a surprisingly stereotypical manner between 12 and 48 wk into definitive UCS. This is remarkable, as UCS has not been reported among prior mouse models of EC, many of which were based on Pten or Trp53 (35, 39–41). These findings thus point to Fbxw7 as a specific driver of UCS.…”

Ovarian insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities

“…Since triple-gene mutant cells were mostly negative for PGR, P4 likely represses endometrial carcinogenesis by acting through stromal cells as found in the normal uterus ( 64 – 69 ). Additionally, normal epithelial cells adjacent to mutant epithelial cells appear to play a critical role in repressing the progression of EECs because aggressive epithelial lesions developed when Pten was mutated in the entire uterine epithelium by Ltf iCr e ( 70 ). To develop preventive and therapeutic treatments for EECs, it is crucial to elucidate the molecular mechanisms underlying the tumor-repressing effects of the normal endometrial environment and steroid hormones.…”