Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease

Abstract

Rapid effects of steroid hormones were discovered in the early 1950s, but the subject was dominated in the 1970s by discoveries of estradiol and progesterone stimulating protein synthesis. This led to the paradigm that steroid hormones regulate growth, differentiation, and metabolism via binding a receptor in the nucleus. It took 30 years to appreciate not only that some cellular functions arise solely from membrane-localized (SRs) actions, but that rapid sex steroid signaling from membrane-localized SRs is a prerequisite for the phosphorylation, nuclear import, and potentiation of the transcriptional activity of nuclear SR counterparts. Here, we provide a review and update on the current state of knowledge of membrane-initiated estrogen (ER), androgen (AR) and progesterone (PR) receptor signaling, the mechanisms of membrane-associated SR potentiation of their nuclear SR homologues, and the importance of this membrane-nuclear SR collaboration in physiology and disease. We also highlight potential clinical implications of pathway-selective modulation of membrane-associated SR.

High GPER expression in triple-negative breast cancer is linked to pro-metastatic pathways and predicts poor patient outcomes

“…However, GPER was detected in tissues and cell lines of not only breast cancer but also other organs lacking ER-α expression 12,13 . Furthermore, GPER was observed to bind E2 directly in several cell lines lacking ER-α 10,39,40 . In clinical series, inverse correlation or non-significant association was also found between GPER and ER-α 41 .…”

Efficacy of glucagon-like peptide-1 and estrogen dual agonist in pancreatic islets protection and pre-clinical models of insulin-deficient diabetes

“…This could reflect the need for intracellular processing of the GLP1-E2 conjugate prior to activate E2 action. Indeed, E2, a steroid, rapidly enters cells to activate signaling cascades in the vicinity of the plasma membrane, 34 and within 1 min of stimulation, E2 reached the nucleus of MIN6 cells to activate EREs. In contrast, GLP1-E2 must be internalized via GLP-1R (likely in endosomes), and activation of EREs from GLP1-E2 required lysosomal degradation.…”

Molecular regulation of prostate cancer by Galectin-3 and estrogen receptor

“…5 Molecular regulatory mechanisms responsible for the expression of the Galectin-3 induced by estrogen signaling in androgen-independent prostate cancer cells 17b-estradiol (E2) impacts normal and malignant tissue development via estrogen receptors ERa (ESR1) and ERb (ESR2), either through ligand-activated transcriptional regulation (genomic pathway) or by triggering cytoplasmic-signaling cascades (rapid action or nongenomic pathway). The possible convergence of genomic and rapid pathways on target genes is an attractive mechanism by which ER can finely regulate the gene expression in different cells (reviewed by 9,58).…”

“…It is important to mention that the promoter region of the human LGALS3 gene contains regulatory elements for several transcription factors (6; reviewed by 7) and ERs may interact with these transcription factors (reviewed by 8). ERs have both classical transcriptional nuclear properties and membrane-initiated rapid action that may function either separately as distinct pathways, or together as a fully integrated network (reviewed by 9). These molecular mechanisms induced by activation of ERs may be involved in the expression of the GAL-3 in androgen-independent prostate cancer cells.…”