Progesterone: The ultimate endometrial tumor suppressor Original paper

What was reviewed?

This review explains how progesterone endometrial tumor suppressor pathways act through progesterone receptors to restrain estrogen-driven growth, drive differentiation, and shape treatment response in endometrial disease. The authors map the roles of the two receptor isoforms, PRA and PRB, describe crosstalk with estrogen signaling, and outline gene networks that control cell cycle arrest, apoptosis, invasion, and immune tone. They summarize why loss of receptor expression or function limits progestin therapy in advanced cancer and show how epigenetic silencing, miRNA control, SUMOylation, and proteasomal degradation can reduce receptor activity. The review does not report microbiome profiling, yet its immune and barrier findings carry clear microbiome relevance because they alter mucosal defenses that guide microbial ecology in the uterus.

Who was reviewed?

The review centers on women with endometrial hyperplasia, type I endometrioid carcinoma, and aggressive type II tumors, with emphasis on how progesterone receptor status predicts response to therapy. It also draws on preclinical work in human endometrial cancer cell lines, xenografts, and multiple mouse and rat models that clarify receptor biology and downstream signaling. Clinical observations include higher response to progestins in PR-rich tumors and brief benefit in recurrent disease, which aligns with gradual receptor loss under treatment pressure. These populations reflect typical clinic cohorts in whom hormonal therapy can reverse hyperplasia, treat early disease in fertility-sparing settings, and complement targeted strategies when tumors keep or regain receptor expression.

Most important findings

Estrogen promotes epithelial proliferation via ER-driven growth signals, including EGF/EGFR, IGF-1, and proto-oncogenes such as c-fos and c-myc, while non-genomic ER activity engages PI3K/Akt. Progesterone counters these inputs through PR-dependent transcription that decreases proliferation, invasion, and inflammation and that induces differentiation and apoptosis. PRB usually drives stronger transcription; PRA can blunt ER action. Progesterone suppresses AP-1 and NF-κB activity, upregulates cyclin-dependent kinase inhibitors p21 and p27, limits c-jun and cyclin D1 promoter activity, and induces Wnt pathway brakes such as DKK1 and FOXO1. Progestin therapy regresses hyperplasia in most cases and treats a subset of primary tumors, yet responses in recurrent disease remain modest. Mechanisms of reduced sensitivity include PRB promoter hypermethylation, miRNA-mediated downregulation, SUMOylation that restrains PR activity, and ligand-triggered MAPK phosphorylation that targets PR for proteasomal degradation.

Key implications

Clinicians can expect the strongest and most durable hormonal responses in PR-expressing, well-differentiated disease and in hyperplasia. You should pair pathology and receptor status with therapy choice, consider fertility-sparing progestin regimens for eligible patients, and anticipate diminishing benefit as receptor expression falls. You should also watch for strategies that restore or enhance PR function, including the use of tamoxifen to induce receptor expression and potential epigenetic approaches to reverse PRB promoter methylation. Because PR signaling quiets AP-1 and NF-κB and strengthens epithelial control of the microenvironment, integration of receptor status with endometrial microbiome sampling could uncover reproducible immune-microbiome signatures for risk stratification and for tracking response during progestin therapy, even though this review offers no direct microbial data.