Androgen receptor as a therapeutic target in endometrial cancer: a narrative review

Endometrial cancer continues to be the most common gynecologic malignancy in the United States. Endometrial tumors frequently express hormonal receptors, making this pathway targeting an attractive anti-cancer treatment. Recent advances have broadened our understanding of the androgen receptor's role in solid tumors beyond prostate cancer. Understanding the significance of androgen receptor signaling and its effects on tumor behavior and therapeutic outcomes in endometrial cancer is important for further clinical development. This review presents inter-connected pathways involving sex hormone-binding globulin, androgens, and androgen receptor signaling in cellular processes related to tumor pathogenesis. Sex hormone-binding globulin regulates androgen levels, influencing aromatase activity and estrogen production, which in turn activates estrogen receptors involved in gene expression promoting cell growth. Concurrently, notch pathway transcription factor forkhead box A1 modulates androgen receptor activity, impacting androgen receptor target gene expression and cell proliferation. Lysin-specific histone demethylases lysine demethylase 4A and lysine demethylase 4B modify chromatin at c-Myc and p27 promoter regions, respectively, affecting gene expression critical for cell-cycle regulation and tumor progression, demonstrating complex regulation of cellular mechanisms by hormone signaling pathways. lysine demethylase 4A interacts with androgen receptor signaling through chromatin remodeling, influencing transcriptional regulation of key cell-cycle genes. The complexity of androgen receptor signaling in endometrial cancer, marked by its varied expression and influence, necessitates a deeper investigation to harness its full therapeutic potential. The exploration of androgen receptor-targeted therapies offers promising avenues for refining treatments and improving outcomes of patients with endometrial cancer. This narrative review synthesizes current evidence on androgen receptor signaling and its therapeutic implications in endometrial cancer. Several potential androgen receptor-targeted approaches are also discussed in the context of future therapeutic development. These possible candidates to call for further development include (1) triple hormonal targeting with androgen receptor inhibitor, aromatase inhibitor, gonadotropin-releasing hormone and agonism, (2) targeting androgen receptor and lysine-specific demethylase 1-dependent forkhead box A1 demethylation, (3) targeting lysine demethylase 4B, (4) gamma secretase inhibitor combination therapy, and (5) combined androgen receptor and immune checkpoint inhibition.