A Causal Link Between Disrupted AKT Signaling and Hyperproliferative Endometrial Diseases

Most endometrial diseases are hyperproliferative and caused by excessive estradiol (E2) signaling, diminished progesterone (P4) signaling, or both. By example, endometriosis, adenomyosis, and type I endometrial cancer are all driven by excessive E2 exposure or aberrant estrogen receptor (ESR1) signaling. Endometriosis is also commonly associated with P4 resistance in which ectopic endometriotic lesions and eutopic endometrium have abnormally low expression of progesterone receptor (PGR). While it is well established that genomic events coordinate many of the most profound and well-studied sex steroid-initiated actions in the endometrium, activation of intracellular phosphorylation cascades, production of rapid calcium transients, changes to luminal epithelial cell height, and edema occur much too rapidly to be caused by the classical pathway, which involves transcription and translation. Work from several laboratories over the past 2 decades has revealed the importance of rapid acting steroid hormone signaling collectively called non-classical signaling. By example, P4 signals rapidly through PGR that is tethered to the plasma membrane by palmitoylate lipid moieties and this activates several phosphorylation cascades (1). Some non-classical E2 signaling events are thought to be mediated by membrane bound ESR1 (mESR1) and mESR2 (1). It is now clear that membrane bound forms of sex steroid receptors (ie, ESR1/2, PGR, androgen receptor) potentiate the actions of their soluble cytosolic/nuclear receptor equivalents through activation of phosphorylation cascades (1, 2). Such phosphorylation cascades result in selective phosphorylation of cytosolic/nuclear isoforms, and this in turn enhances/reduces protein-protein interactions with transcriptional co-activators/repressors to fine-tune genomic responses.