GREB1 as a Context-Dependent Molecular Switch in Endometrial Estrogen-Progesterone Crosstalk: From Physiological...

In this narrative review, we summarize current evidence regarding the endometrium undergoes cyclic remodeling driven by estrogen (E2) and progesterone (P4) signaling, with precise coordination essential for receptivity and pregnancy establishment. GREB1, initially identified as an estrogen-responsive co-activator in breast cancer, plays a pivotal, context-dependent role in endometrial biology. In normal physiology, GREB1 predominantly supports progesterone signaling: it is directly induced by progesterone receptor (PR) and functions as a critical co-activator that reinforces PR-dependent transcription, enabling stromal decidualization, implantation window formation, and receptivity. Genetic deletion or silencing of GREB1 selectively impairs progesterone-driven responses while largely sparing estrogen-mediated proliferation. In pathological conditions such as endometriosis, the regulatory balance shifts dramatically. Estrogen dominance and progesterone resistance redirect GREB1 toward an ERα-centered feedforward loop, amplifying proliferative, invasive, and angiogenic gene programs that promote lesion persistence and progression. This bidirectional feedforward mechanism with steroid receptors explains GREB1's opposing roles in health and disease. The findings position GREB1 as a promising biomarker of tissue-level progesterone responsiveness in infertility and as a selective therapeutic target for estrogen-driven endometrial disorders, potentially allowing disruption of pathological amplification while preserving physiological function. As a narrative review, this article synthesizes current knowledge while highlighting areas requiring further systematic investigation.