Cell-Autonomous AR Dependence in Luminal Prostatic Epithelium Governs Survival and Lineage Plasticity

Prostate cancer resembles differentiated secretory luminal cells and shows cell-autonomous dependence on androgen receptor (AR) signaling, yet normal luminal cells are often considered dependent on paracrine stromal AR signaling. To resolve this, we conditionally deleted <i>Ar</i> in luminal acinar cells <i>in vivo</i> . <i>Ar</i> -deleted luminal cells persisted short-term, in contrast to the rapid regression observed after castration, but were impaired in regeneration and progressively lost. Their depletion was accompanied by replacement through basal-to-luminal differentiation of AR intact basal cells. Transcriptomic and chromatin profiling showed cell-autonomous suppression of the secretory program with induction of stemness, inflammatory, and epithelial-to-mesenchymal transition signatures after AR loss. Mechanistically, the MAP kinase pathway and downstream AP-1 transcription factors were activated and functionally validated, and MAP kinase inhibition selectively depleted AR-deleted luminal cells, indicating a compensatory survival pathway. These findings define intrinsic roles for luminal AR in maintaining differentiation, restraining plasticity, and sustaining regeneration and homeostatic turnover, providing a mechanistic basis for AR dependence in prostate cancer.