Androgen receptor may promote tumor progression via TTF-1/EGFR pathway in metastatic nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is prevalent in Southeast Asia, including Taiwan. It exhibits higher morbidity as well as mortality in males than in females. However, the role of the androgen receptor (AR) in NPC remains unclear. In this study, AR expression was detected in most NPC cell lines and patient-derived xenografts. Treatment with enzalutamide, an antiandrogen, substantially inhibited patient-derived xenografts growth and demonstrated additive antitumor effects when combined with chemotherapy in AR-positive models. Additionally, transcriptome analysis following enzalutamide treatment revealed activation of hypoxia-inducible factor-1, steroid hormone, and AR pathways, alongside suppression of interferon and tumor necrosis factor pathways. Protein analysis further supported these transcriptomic changes. In AR-overexpressing NPC-B13 cells, AR appeared to regulate thyroid transcription factor-1 (TTF-1, encoded by NKX2-1 gene) and its downstream target epidermal growth factor receptor (EGFR), thereby promoting cancer cell proliferation. Furthermore, chromatin immunoprecipitation suggested that AR may directly bind to the NKX2-1 promoter to upregulate its mRNA expression. Under AR overexpression, Epstein-Barr virus (EBV) remained in a latent state, accompanied by suppression of lytic gene expression. Additionally, Epstein-Barr nuclear antigen-1 enhanced AR transactivation in a dose-dependent manner in NPC cell line reporter assays. Among 96 metastatic NPC tumor samples, AR expression was observed in 35 cases (36.5%), predominantly in males (33/83, 39.8%). AR expression correlated with poorer overall survival, with statistical significance noted in the full cohort and particularly in male patients. This study suggests that AR may promote metastatic NPC progression via the TTF-1/EGFR signaling pathway and interact with EBV to influence disease behavior, especially in males.