FOXA2 overexpression induces prostate tumors with mixed adenocarcinoma and neuroendocrine histology

Following prolonged androgen receptor (AR)-targeted therapy, approximately 20% of castration-resistant prostate cancers (CRPC) progress to AR-independent subtypes. This includes neuroendocrine prostate cancer (NEPC), a highly aggressive variant with dismal clinical outcomes and limited treatment options. The pioneer transcription factor FOXA2 has been shown to drive this neuroendocrine transdifferentiation (NET), yet the precise histological characteristics of FOXA2-driven tumors remain poorly defined. In this study, we demonstrate that FOXA2 overexpression in both xenograft and allograft prostate cancer models induced heterogeneous tumors with a mixed histology. Notably, FOXA2-expressing tumors developed distinct NEPC foci characterized by poorly differentiated histopathology, neuroendocrine gene expression, and significantly elevated Ki-67 proliferation indices compared to adjacent adenocarcinoma regions. Together, these findings validate FOXA2 as a master regulator of lineage plasticity and NEPC transformation in vivo and underscore the clinical relevance of FOXA2 overexpression models in studying NEPC transformation.