{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE339nnn/GSE339459/"]},"type":"primary"},"statusCodeValue":200,"statusCode":"OK"}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE339459"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"5β-Dihydrotestosterone and mutant androgen receptor vulnerability in prostate cancer","description":"BACKGROUND Bipolar androgen therapy (BAT) exploits the paradoxical vulnerability of castration-resistant prostate cancer (CRPC) to supraphysiologic androgen, but current BAT uses testosterone (T), which broadly activates wild-type androgen receptor (AR) in normal androgen-responsive tissues and can cause systemic androgenic effects. 5β-Dihydrotestosterone (5β-DHT), a naturally occurring T metabolite, has been considered androgenically inactive because of weak wild-type AR activity. Here, we examined whether 5β-DHT and related 5β-reduced metabolites activate mutant AR signaling and reproduce BAT-like growth suppression. METHODS Six 5β-reduced T metabolites were evaluated in C4-2 and LNCaP prostate cancer cells under androgen-depleted and BAT-like conditions. AR dependence and mutant-specific activity were assessed using enzalutamide, AR-null PC-3 cells, and PC-3 cells expressing AR-W742C or AR-H875Y. Cell proliferation, AR-responsive reporter activity, RT-qPCR, RNA sequencing with gene set enrichment analysis, immunoblotting, and senescence-associated β-galactosidase staining were used to characterize ligand responses. RESULTS At nanomolar concentrations, 5β-DHT and 3β-etiocholanediol (3β-ecdiol) induced AR target genes and promoted AR-dependent C4-2 and LNCaP growth, although less potently than T. RNA sequencing showed that both metabolites activated the T-regulated AR transcriptional program with smaller differentially expressed gene footprints. At high concentrations, 5β-DHT, but not the weaker agonist 3β-ecdiol or progesterone-class steroids, suppressed C4-2 and LNCaP proliferation. High-dose 5β-DHT also activated AR and suppressed growth in PC-3 cells expressing AR-W742C or AR-H875Y, whereas AR-null PC-3 cells were unaffected. High-dose 5β-DHT enriched androgen-response and senescence programs, suppressed G2M, E2F, and MYC-associated pathways, increased p21, p27, and p57, reduced RB phosphorylation and SKP2, and induced senescence-associated β-galactosidase activity.","dates":{"publication":"2026/08/08"},"accession":"GSE339459","cross_references":{"GSM":["GSM9895982","GSM9895981","GSM9895980","GSM9895989","GSM9895988","GSM9895987","GSM9895986","GSM9895985","GSM9895984","GSM9895983","GSM9895993","GSM9896004","GSM9896003","GSM9895992","GSM9896002","GSM9895991","GSM9895990","GSM9896001","GSM9896000","GSM9895999","GSM9895998","GSM9896009","GSM9896008","GSM9895997","GSM9896007","GSM9895996","GSM9895995","GSM9896006","GSM9896005","GSM9895994"],"GPL":["24676"],"GSE":["339459"],"taxon":["Homo sapiens"]}}