Telapristone Acetate

To explore the diagnostic biomarkers for diagnosing endometriosis.

Endometriosis is a benign, progressive, estrogen-dependent gynecological disorder that has highly variant prevalence. Therefore, it is essential to develop reliable diagnostic biomarkers for endometriosis diagnosis.

To explore the diagnostic biomarkers for endometriosis diagnosis.

Based on transcriptome data from GSE145701, we identified potential therapeutic targets through the intersection of endometriosis-related genes from weighted gene correlation network analysis (WGCNA) and differential expression analysis. Aprotein-protein interaction (PPI) was constructed. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed for functional enrichment analysis. The intersection of hub genes from topological analysis and module genes from module-based network analysis were selected as core targets, which were used for diagnostic model construction. Its robustness was validated using GSE7305 and GSE134056. Associations of core targets with immune characteristics and pathways were further evaluated. Molecular docking was employed to evaluate the docking affinity between core targets and drugs. Additionally, western blot and quantitative real-time polymerase chain reaction were also carried out to validate molecular docking results.

A diagnostic model was constructed using 7 core targets, which had a high diagnostic ability for endometriosis. CTSK was positively correlated with immune scores, while CDH2 was negatively correlated with immune scores. CTSK, HGF, and EPCAM were positively correlated with energy metabolism and inflammation-related pathways, while RUNX2, FN1, NCAM1, and CDH2 were positively correlated with epithelial-to-mesenchymal transition (EMT) and unfolded protein response (UPR). Moreover, FN1 had good docking affinity with Elagolix, Esmya, and Proellex. NCAM1 might be a promising target modulated by Elagolix. In vitro experiment revealed that the expression of FN1 in human normal endometrial cell lines (hEEC) gradually decreased with the increase of Esmya concentration, indicating that FN1 was a target for Esmya.

These results may facilitate the in-depth understanding of the development of endometriosis, and guide early diagnostic as well as clinical treatments for patients with endometriosis.

The ovarian hormones estrogen and progesterone (EP) are implicated in breast cancer causation. A specific consequence of progesterone exposure is the expansion of the mammary stem cell (MSC) and luminal progenitor (LP) compartments. We hypothesized that this effect, and its molecular facilitators, could be abrogated by progesterone receptor (PR) antagonists administered in a mouse model.

Ovariectomized FVB mice were randomized to 14 days of treatment: sham, EP, EP + telapristone (EP + TPA), EP + mifepristone (EP + MFP). Mice were then sacrificed, mammary glands harvested, and mammary epithelial cell lineages separated by flow cytometry using cell surface markers. RNA from each lineage was sequenced and differential gene expression was analyzed using DESeq. Quantitative PCR was performed to confirm the candidate genes discovered in RNA seq. ANOVA with Tukey post hoc analysis was performed to compare relative expression. Alternative splicing events were examined using the rMATs multivariate analysis tool.

Significant increases in the MSC and luminal mature (LM) cell fractions were observed following EP treatment compared to control (p < 0.01 and p < 0.05, respectively), whereas the LP fraction was significantly reduced (p < 0.05). These hormone-induced effects were reversed upon exposure to TPA and MFP (p < 0.01 for both). Gene Ontology analysis of RNA-sequencing data showed EP-induced enrichment of several pathways, with the largest effect on Wnt signaling in MSC, significantly repressed by PR inhibitors. In LP cells, significant induction of Wnt4 and Rankl, and Wnt pathway intermediates Lrp2 and Axin2 (confirmed by qRTPCR) were reversed by TPA and MFP (p < 0.0001). Downstream signaling intermediates of these pathways (Lrp5, Mmp7) showed similar effects. Expression of markers of epithelial-mesenchymal transition (Cdh1, Cdh3) and the induction of EMT regulators (Zeb1, Zeb2, Gli3, Snai1, and Ptch2) were significantly responsive to progesterone. EP treatment was associated with large-scale alternative splicing events, with an enrichment of motifs associated with Srsf, Esrp, and Rbfox families. Exon skipping was observed in Cdh1, Enah, and Brd4.

PR inhibition reverses known tumorigenic pathways in the mammary gland and suppresses a previously unknown effect of progesterone on RNA splicing events. In total, our results strengthen the case for reconsideration of PR inhibitors for breast cancer prevention.