Androgen Receptor and Estrogen Receptor signaling pathways (AR/ER signaling)

The Androgen Receptor (AR) and Estrogen Receptor (ER) signaling pathways are central regulators of cellular growth, differentiation, and homeostasis, particularly within reproductive and endocrine tissues [1, 4]. Both receptors function as ligand-activated transcription factors that, upon binding to steroid hormones such as testosterone or estradiol, translocate to the nucleus to regulate the expression of target genes involved in cell cycle progression and survival [10, 14]. In many cancers, most notably breast and prostate malignancies, these pathways are frequently co-expressed and engage in significant molecular crosstalk that can either inhibit or promote tumorigenesis depending on the cellular context [4, 7]. For example, in ER-positive breast cancer, AR signaling often acts as a tumor suppressor by redistributing ER and its co-activators on chromatin, thereby inhibiting ER-driven growth [4, 11]. Conversely, dysregulation of these pathways is a primary driver of endocrine resistance, where one pathway may compensate for the inhibition of the other [12, 13]. Therapeutic targeting of these pathways remains a cornerstone of oncology, utilizing a range of agents including competitive antagonists, selective receptor modulators, and inhibitors of ligand synthesis [11, 15]. Understanding the intricate balance between AR and ER signaling is crucial for the development of effective combination therapies and for overcoming resistance in hormone-dependent diseases [13, 15].

Other names

AR/ER crosstalkSteroid hormone receptor signalingAndrogen and estrogen receptor pathwaysAR and ER signaling

Drugs targeting these pathways primarily act as competitive antagonists or agonists that bind to the ligand-binding domains of the Androgen Receptor (AR) and Estrogen Receptor (ER). This binding prevents the association of natural steroid hormones, thereby inhibiting receptor dimerization, nuclear translocation, and the subsequent activation of hormone-responsive elements (HREs) in the genome [11, 14]. Some therapeutic strategies also involve the use of selective estrogen receptor degraders (SERDs) or proteolysis-targeting chimeras (PROTACs) to induce receptor degradation, or aromatase inhibitors to deplete the supply of endogenous estrogen [12, 15].