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Patients with enlarged prostates are treated with 5\u2010alpha reductase inhibitors (5ARIs) to shrink prostate volume by blocking the conversion of testosterone to dihydrotestosterone (DHT). A reduction in DHT levels can elicit atrophy and apoptosis of prostate secretory luminal cells, which results in a favorable clinical response characterized by improved lower urinary tract symptoms. However, the histologic response to 5ARI treatment is often heterogeneous across prostate acini and lower urinary tract symptoms can persist to require surgical intervention. We used two spatial profiling approaches to characterize gene expression changes across histologically normal and atrophied regions in prostates from 5ARI\u2010treated men. Objective transcriptomic profiling using the Visium spatial gene expression platform showed that 5ARI\u2010induced atrophy of prostate luminal cells correlated with reduced androgen receptor signaling and increased expression of urethral club cell genes including\n                    <jats:italic>LTF<\/jats:italic>\n                    ,\n                    <jats:italic>PIGR<\/jats:italic>\n                    ,\n                    <jats:italic>OLFM4<\/jats:italic>\n                    ,\n                    <jats:italic>SCGB1A1<\/jats:italic>\n                    , and\n                    <jats:italic>SCGB3A1<\/jats:italic>\n                    . Prostate luminal cells within atrophied acini adapted to decreased DHT conditions by increasing NF\u2010\u03baB signaling and anti\u2010apoptotic\n                    <jats:italic>BCL2<\/jats:italic>\n                    expression, which may explain their survival. Using GeoMx digital spatial profiling with a probe set to assess ~18\u2009000 RNA targets, we confirmed that atrophied acini expressing\n                    <jats:italic>SCGB3A1<\/jats:italic>\n                    displayed higher levels of club cell markers compared with histologically normal acini with\n                    <jats:italic>NKX3\u20101<\/jats:italic>\n                    expression. In addition, club\u2010like cells within regions of 5ARI\u2010induced atrophy closely resembled true club cells from the prostatic urethra. A comparison of histologically normal regions from 5ARI\u2010treated men and histologically normal regions from untreated men revealed few transcriptional differences. Taken together, our results describe a heterogeneous response to 5ARI treatment where cells in atrophied acini undergo an adaptation from a prostate secretory luminal to a club cell\u2010like state in response to 5ARI treatment. \u00a9 2021 The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.5857","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T11:10:07Z","timestamp":1639998607000},"page":"427-441","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["5\u2010Alpha reductase inhibitors induce a prostate luminal to club cell transition in human benign prostatic hyperplasia"],"prefix":"10.1002","volume":"256","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0587-9558","authenticated-orcid":false,"given":"Diya B","family":"Joseph","sequence":"first","affiliation":[{"name":"Department of Urology UT Southwestern Medical Center  Dallas TX 75390 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7772-9578","authenticated-orcid":false,"given":"Gervaise H","family":"Henry","sequence":"additional","affiliation":[{"name":"Department of Urology UT Southwestern Medical Center  Dallas TX 75390 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1966-6035","authenticated-orcid":false,"given":"Alicia","family":"Malewska","sequence":"additional","affiliation":[{"name":"Department of Urology UT Southwestern Medical Center  Dallas TX 75390 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey C","family":"Reese","sequence":"additional","affiliation":[{"name":"Southwest Transplant Alliance  Dallas TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6385-5397","authenticated-orcid":false,"given":"Ryan 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