{"entity":{"id":"paper-visakorpi-androgen-receptor-amplification-nat-genet-1995","kind":"paper","name":"In vivo amplification of the androgen receptor gene and progression of human prostate cancer","aka":["Visakorpi 1995","AR gene amplification prostate cancer"],"tldr":"When hormone treatment stops working, the cancer often has not stopped caring about the hormone. In a third of tumours that came back on treatment, the cell had simply made extra copies of the androgen receptor gene so it could live on the tiny amount of hormone left.","summary":"Tapio Visakorpi and colleagues in Tampere used comparative genomic hybridisation on tumours taken before androgen deprivation and again when they recurred on it, in the same patients. Amplification of the Xq11-q13 region, which carries the androgen receptor gene, appeared in the recurrent tumours and in none of the pre-treatment samples from the same men.\n\nThe finding reframed what castration resistance is. The old name, hormone-refractory prostate cancer, implied that the tumour had stopped using the androgen pathway. This paper said the opposite: the tumour had adapted to keep using it in a low-androgen environment. That is why abiraterone, enzalutamide, apalutamide and darolutamide work at all, and why they were built.","asOf":"2026-09-25","links":[{"label":"Nat Genet 1995","url":"https://doi.org/10.1038/ng0495-401"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/7795646/"}],"tags":["prostate-evidence"],"related":["paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","paper-huggins-hodges-castration-serum-phosphatases-prostate-1941","prostate-roadmap"],"cancers":["prostate","prostate-mcrpc"],"sections":["hormonal","targeted-therapy"],"technologies":["cytogenetics-fish"],"targets":["androgen-receptor"],"drugs":[],"companies":[],"institutions":[],"pathways":["ar-signaling","prostate-cancer-signalling"],"terms":["castration-resistance","adt","gene-amplification","resistance","intraductal-carcinoma-prostate"],"trials":[],"people":[],"bottlenecks":["b-resistance","b-tumor-heterogeneity"],"keyPapers":[],"journals":["nature-genetics"],"dependsOn":[],"notes":[],"journal":"Nature Genetics","year":1995,"doi":"10.1038/ng0495-401","pmid":"7795646","authors":"Visakorpi T, Hyytinen E, Koivisto P, et al.","paperType":"basic","findings":["High-level androgen receptor amplification in 7 of 23 (30 percent) tumours recurring during androgen deprivation therapy.","No amplification in any of the specimens taken from the same patients before therapy.","Amplification of the Xq11-q13 region, where the androgen receptor gene sits, is common in tumours recurring on androgen deprivation."],"whatItMeans":"The first evidence that resistance to hormone therapy in prostate cancer is an adaptation of the target rather than an escape from it, which is why the field kept building better androgen receptor drugs instead of abandoning the pathway.","caveats":["23 recurrent tumours from one centre; the 30 percent figure is not a population estimate.","Comparative genomic hybridisation detects amplification, not the other routes to the same end (receptor mutation, splice variants, intratumoural androgen synthesis) that were described later.","Amplification explains part of castration resistance; the AR-independent part, described in the lineage plasticity papers, is not addressed here."],"changedPractice":false,"participants":23},"route":"/key-papers/paper-visakorpi-androgen-receptor-amplification-nat-genet-1995/","neighbours":{"paper":[{"id":"paper-huggins-hodges-castration-serum-phosphatases-prostate-1941","kind":"paper","name":"Huggins and Hodges 1941: the effect of castration, of oestrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate","route":"/key-papers/paper-huggins-hodges-castration-serum-phosphatases-prostate-1941/"},{"id":"paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","kind":"paper","name":"Molecular determinants of resistance to antiandrogen therapy","route":"/key-papers/paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004/"}],"roadmap":[{"id":"prostate-roadmap","kind":"roadmap","name":"Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch","route":"/roadmaps/prostate-roadmap/"}],"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"section":[{"id":"hormonal","kind":"section","name":"Hormonal Therapy","route":"/fronts/hormonal/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"cytogenetics-fish","kind":"technology","name":"Cytogenetics and FISH","route":"/technologies/cytogenetics-fish/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"prostate-cancer-signalling","kind":"pathway","name":"Prostate cancer (KEGG map)","route":"/pathways/prostate-cancer-signalling/"}],"term":[{"id":"adt","kind":"term","name":"Androgen deprivation therapy (ADT)","route":"/terms/adt/"},{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"gene-amplification","kind":"term","name":"Gene amplification and copy-number change","route":"/terms/gene-amplification/"},{"id":"intraductal-carcinoma-prostate","kind":"term","name":"Intraductal carcinoma of the prostate (IDC-P)","route":"/terms/intraductal-carcinoma-prostate/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}],"journal":[{"id":"nature-genetics","kind":"journal","name":"Nature Genetics","route":"/journals/nature-genetics/"}],"idea":[{"id":"idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2","kind":"idea","name":"Take high-dose testosterone to phase 3, with progression-free survival through the second line as the primary endpoint","route":"/ideas/idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2/"}],"biomarker":[{"id":"ar-amplification","kind":"biomarker","name":"AR amplification (gene and upstream enhancer)","route":"/biomarkers/ar-amplification/"}]}}