ORF48-04 - Targeting Steroid Hormone Receptor Crosstalk for Novel Therapeutic Strategies in Endometrial Cancer

Background: Endometrial cancer (EC) incidence and mortality are increasing, driven in part by aggressive, non-endometrioid histologic subtypes with limited therapeutic options. Steroid hormone receptors including the estrogen receptor (ER), androgen receptor (AR), and glucocorticoid receptor (GR) are central regulators of uterine biology, yet their cooperative signaling roles in EC progression remain poorly defined. While ER is a dominant driver of low-grade endometrioid tumors, emerging evidence implicates AR and GR in proliferation, stress response, and therapeutic resistance in high-grade disease. Because steroid receptors share co-regulators and downstream signaling pathways, receptor crosstalk may sustain tumor growth and limit the efficacy of single-agent endocrine therapies.

Methods: We integrated genome-wide transcriptional profiling with functional assays to define cooperative steroid receptor signaling across EC histologies. Receptor activation and inhibition studies were performed in cell line models representing low-grade and high-grade EC subtypes. To enhance translational relevance, we generated and characterized a panel of patient-derived organoid (PDO) models that preserve tumor-specific histologic and molecular heterogeneity. Receptor-dependent transcriptional programs, pathway activation, and growth phenotypes were assessed across models.

Results: Transcriptomic analyses revealed histology-specific steroid receptor crosstalk, with cooperative and competitive ER, AR, and GR transcriptional programs regulating distinct oncogenic pathways. Combined receptor activation synergistically enhanced proliferation-associated signaling, whereas dual receptor inhibition produced synergistic growth suppression in a subtype-dependent manner. High-grade EC models demonstrated persistent dependence on AR and GR signaling despite ER loss.

Conclusions: These data establish steroid hormone receptor crosstalk as a key driver of EC progression and identify histology-specific endocrine vulnerabilities. By mapping cooperative steroid receptor signaling across clinically relevant models, this work provides a mechanistic foundation for rational dual-receptor endocrine strategies and a translational framework for personalized therapy in patients with advanced or refractory EC.