Progesterone Inhibits Epithelial-to-Mesenchymal Transition in Endometrial Cancer

Abstract

BackgroundEvery year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT).Methodology and Principal FindingsParaffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa(IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB(IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling.ConclusionIntact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.

IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden

“…Finally, activation of the IL6 signaling cascade results in the de novo generation of CSCs through induction of EMT (38). The latter is also in agreement with our previous study, where increased expression levels of IL6 and STAT3 were detected in endometrial tumors displaying EMT features (39). Our RT-qPCR analysis of several EMT-related genes in endometrial cancer cell lines identified differential expression between the ALDH hi and ALDH lo subpopulations of the HEC1A cell line only in the case of TWIST1 and TWIST2 ( Supplementary Fig.…”

Antisecretive and Antitumor Activity of Abiraterone Acetate in Human Adrenocortical Cancer: A Preclinical Study

“…Interestingly, progesterone contributes to the dynamic modification of the endometrial epithelium during the menstrual cycle by inhibiting Wnt/beta-catenin signaling, which is also required for maintaining endometrial homeostasis and for contrasting progression toward hyperplasia and carcinogenesis [29,30]. We found that AA induced an increase in progesterone levels and prevented the nuclear accumulation of beta-catenin in NCI-H295R cells.…”

Comparative characteristics of the transcriptional activity of CDH1, CTNNB1, VEGFA genes and expression of proteins E-cadherin, β-catenin and VEGFA, coded by these genes in metastatic and non-metastatic endometrioid endometrial carcinoma

“…The loss of E-cadherin expression in EEC is associated not only with the CDH1 gene mutations [17], but also with CDH1 promoter hypermethylation [18] and dysregulation of the proteins, which normally inhibit the E-cadherin expression. The loss of E-cadherin expression is a poor prognostic factor for the patients with EEC [10], because this loss is associated with the phenomenon of epithelial-mesenchymal transformation, which includes the loss of apical-basal polarity of the cancer cells, the increasing of the mesenchymal integrins synthesis by these cells, the migration of the tumor cells into the adjacent tissues and also the tumor metastasis [19].…”