Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen deprivation remain poorly described, despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that we called LSC^med according to their FACS profile (Lin^- /Sca-1⁺ /CD49f^med ). Here, we investigated the prevalence and castration resistance of LSC^med in various mouse models of prostate tumourigenesis (Pb-PRL, Pten^pc-/- , and Hi-Myc mice). LSC^med prevalence is low (∼8%, similar to WT) in Hi-Myc mice, where prostatic androgen receptor signalling is unaltered, but is significantly higher in the two other models, where androgen receptor signalling is decreased, rising up to more than 80% in Pten^pc-/- prostates. LSC^med tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration. The tumour-initiating properties of LSC^med from Pten^pc-/- mice were demonstrated by regeneration of tumours in vivo. Transcriptomic analysis revealed that LSC^med represent a unique cell entity as their gene expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signalling is markedly decreased, explaining why LSC^med tolerate androgen deprivation. This also illuminates why Pten^pc-/- tumours are castration-resistant since LSC^med represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSC^med on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSC^med in various mouse prostate specimens. In castrated Pten^pc-/- prostates, there was significant proliferation of CK4⁺ cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSC^med as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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