Forkhead transcription factor FOXO1 is a direct target of progestin to inhibit endometrial epithelial cell growth.

PURPOSE AND EXPERIMENTAL DESIGN: Despite the therapeutic utility of progestin in invasive and preinvasive endometrial neoplasias, the molecular mechanisms through which it exerts inhibitory effects on endometrial epithelial growth are largely unknown. The aim of the study was to clarify the molecular mechanisms of progestin action to endometrial epithelial cells using originally established in vitro and in vivo treatment models for immortalized and transformed endometrial epithelial cell lines that express progesterone receptor. RESULTS: In this model, progestin effectively inhibited the cell growth, inducing G0/G1 arrest rather than apoptosis without p21/WAF-1 induction. Using DNA microarray analysis, we identified 24 genes whose expression increased more than 10-fold on progestin treatment. Of these genes, we paid special attention to forkhead box transcription factor FOXO1, known as a key gene for endometrial decidualization. Progestin markedly induced FOXO1 gene expression mainly in the nuclei in vitro and in vivo. This induction was not due to the canonical activation of FOXO1 via protein dephosphorylation but due to FOXO1 promoter activation and mRNA induction. siRNA inhibition of FOXO1 significantly attenuated the effects of progestin to inhibit endometrial epithelial cell growth. Disrupting Akt activity by the introduction of the dominant negative form of Akt increased nuclear FOXO1 accumulation and enhanced the effect of progestin. CONCLUSION: These findings suggest that FOXO1 is a direct target of progestin, implicating novel molecular mechanisms of progestin to eradicate endometrial neoplasia.

Gene expression profiles and microsatellite instability in uterine corpus endometrioid adenocarcinoma.

AIM: We examined corpus cancer to identify whether there are distinctive patterns of global gene expression and microsatellite instability, and to gain molecular understanding of its carcinogenesis and progression. METHODS: Thirty endometrioid corpus cancer tissue samples (21 of G1 and nine of G2/3) were analyzed by cDNA microarray based on 637 cancer-associated genes and by a polymerase chain reaction method for microsatellite instability. RESULT: Of the 30 cases, 10 (33%) were recognized as having microsatellite instability. In all cases, four genes were overexpressed and five genes were underexpressed. There were six microsatellite instability-specific overexpressed or high-frequency genes and 15 underexpressed or low-frequency genes. Furthermore, we identified several genes by grade analysis. CONCLUSIONS: These results may be useful resources for the development of diagnostic assays, prognostic factors, or therapeutic targets for corpus endometrioid cancer.