# Androgen receptor signalling

Source: https://onco.cc/pathways/ar-signaling/  
OnCo record `ar-signaling` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Androgen receptor signalling is prostate cancer's engine. Testosterone becomes DHT, binds the androgen receptor, and drives growth genes. Castration removes the fuel; newer pills block the receptor or the enzyme that makes fuel inside the tumour.

## Summary

Testicular testosterone (and adrenal precursors converted intratumourally via CYP17A1) is reduced to DHT by 5α-reductase and binds AR, which translocates to the nucleus and drives PSA, TMPRSS2-ERG, and proliferation genes. GnRH agonists/antagonists shut testicular production; abiraterone blocks CYP17A1; enzalutamide, apalutamide, darolutamide block AR. Castration resistance arises via AR amplification, ligand-binding mutations, splice variants (AR-V7 lacks the ligand domain), glucocorticoid receptor substitution, and lineage plasticity to neuroendocrine phenotype.

## Fields

- Kind: Pathway
- Last checked: 2026-09-04
- Analogy: Same key-and-lock idea as oestrogen: castration stops making keys, abiraterone shuts the tumour's own key factory, enzalutamide blocks the lock. AR-V7 is a lock with no keyhole that is permanently open.
- Interventions: GnRH agonists/antagonists (leuprolide, relugolix); CYP17A1 inhibitor abiraterone; AR antagonists enzalutamide, apalutamide, darolutamide; PARP inhibitors + ARPI in HRR-mutant disease; capivasertib + abiraterone in PTEN-deficient; AR degraders, N-terminal domain inhibitors (trials)

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Androgen_receptor
- Wikipedia: https://en.wikipedia.org/wiki/Androgen_receptor

## Connected records

- cancers: [Prostate cancer](https://onco.cc/cancers/prostate/), [Salivary gland cancers](https://onco.cc/cancers/salivary-gland/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Androgen deprivation & AR pathway inhibitors](https://onco.cc/technologies/androgen-deprivation/)
- targets: [AKT](https://onco.cc/targets/akt/), [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [PARP](https://onco.cc/targets/parp/), [PSMA](https://onco.cc/targets/psma/)
- drugs: [Abiraterone acetate](https://onco.cc/drugs/abiraterone/), [Apalutamide](https://onco.cc/drugs/apalutamide/), [Bicalutamide](https://onco.cc/drugs/bicalutamide/), [Capivasertib](https://onco.cc/drugs/capivasertib/), [Darolutamide](https://onco.cc/drugs/darolutamide/), [Enzalutamide](https://onco.cc/drugs/enzalutamide/), [Niraparib](https://onco.cc/drugs/niraparib/), [Olaparib](https://onco.cc/drugs/olaparib/), [Relugolix](https://onco.cc/drugs/relugolix/), [Talazoparib](https://onco.cc/drugs/talazoparib/)
- terms: [AR-V7 splice variant](https://onco.cc/terms/ar-v7/), [Castration-resistant prostate cancer (CRPC)](https://onco.cc/terms/castration-resistance/), [Hormone therapy](https://onco.cc/terms/hormone-therapy/), [Signalling pathway](https://onco.cc/terms/signalling-pathway/)
- key papers: [Androgen receptor pathway-independent prostate cancer is sustained through FGF signalling](https://onco.cc/key-papers/paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017/), [AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer](https://onco.cc/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/), [Circulating tumour DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer](https://onco.cc/key-papers/paper-annala-ctdna-resistance-abiraterone-enzalutamide-cancer-discov-2018/), [Concordance of circulating tumour DNA and matched metastatic tissue biopsy in prostate cancer](https://onco.cc/key-papers/paper-wyatt-ctdna-tissue-concordance-mcrpc-jnci-2017/), [Differences in prostate cancer genomes by self-reported race](https://onco.cc/key-papers/paper-stopsack-prostate-genomes-by-race-ccr-2022/), [Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer](https://onco.cc/key-papers/paper-traina-enzalutamide-ar-tnbc-jco-2018/), [Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer](https://onco.cc/key-papers/paper-barbieri-spop-foxa1-med12-prostate-nat-genet-2012/), [Genomic analysis of circulating tumour DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms](https://onco.cc/key-papers/paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021/), [Genomic correlates of clinical outcome in advanced prostate cancer](https://onco.cc/key-papers/paper-abida-genomic-correlates-outcome-mcrpc-pnas-2019/), [Genomic hallmarks and structural variation in metastatic prostate cancer](https://onco.cc/key-papers/paper-quigley-structural-variation-mcrpc-cell-2018/), [Genomics of lethal prostate cancer at diagnosis and castration resistance](https://onco.cc/key-papers/paper-mateo-genomics-lethal-prostate-diagnosis-castration-resistance-jci-2020/), [Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies](https://onco.cc/key-papers/paper-lehmann-tnbc-subtypes-jci-2011/), [In vivo amplification of the androgen receptor gene and progression of human prostate cancer](https://onco.cc/key-papers/paper-visakorpi-androgen-receptor-amplification-nat-genet-1995/), [Integrative genomic profiling of human prostate cancer](https://onco.cc/key-papers/paper-taylor-integrative-genomic-profiling-cancer-cell-2010/), [IPATential150: ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-ipatential150-ipatasertib-abiraterone-pten-lancet-2021/), [Molecular determinants of resistance to antiandrogen therapy](https://onco.cc/key-papers/paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004/), [Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-labrecque-mcrpc-phenotypes-jci-2019/), [Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer](https://onco.cc/key-papers/paper-taplin-ar-mutation-androgen-independent-prostate-nejm-1995/), [Nuclear-localised androgen receptor splice variant 7 in circulating tumour cells as a predictive biomarker in castration-resistant prostate cancer](https://onco.cc/key-papers/paper-scher-nuclear-arv7-taxane-vs-arsi-jama-oncol-2018/), [Oncogenic genomic alterations, clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer](https://onco.cc/key-papers/paper-stopsack-mcspc-genomic-alterations-outcomes-ccr-2020/), [Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer](https://onco.cc/key-papers/paper-gucalp-bicalutamide-ar-positive-tbcrc011-ccr-2013/), [PROPHECY: prospective multicentre validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer](https://onco.cc/key-papers/paper-prophecy-arv7-validation-jco-2019/), [PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate](https://onco.cc/key-papers/paper-ferraldeschi-pten-protein-loss-abiraterone-eur-urol-2015/), [Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance](https://onco.cc/key-papers/paper-ku-rb1-trp53-lineage-plasticity-science-2017/), [Reciprocal feedback regulation of PI3K and androgen receptor signalling in PTEN-deficient prostate cancer](https://onco.cc/key-papers/paper-carver-pi3k-ar-reciprocal-feedback-prostate-cancer-cell-2011/), [Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer](https://onco.cc/key-papers/paper-tomlins-tmprss2-ets-fusion-science-2005/), [SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer](https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/), [SU2C-PCF: integrative clinical genomics of advanced prostate cancer](https://onco.cc/key-papers/paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015/), [Substantial interindividual and limited intraindividual genomic diversity among tumours from men with metastatic prostate cancer](https://onco.cc/key-papers/paper-kumar-interindividual-genomic-diversity-metastatic-prostate-nat-med-2016/), [TCGA: the molecular taxonomy of primary prostate cancer](https://onco.cc/key-papers/paper-tcga-molecular-taxonomy-primary-prostate-cell-2015/), [The mutational landscape of lethal castration-resistant prostate cancer](https://onco.cc/key-papers/paper-grasso-mutational-landscape-lethal-crpc-nature-2012/), [The TMPRSS2-ERG rearrangement, ERG expression and prostate cancer outcomes: a cohort study and meta-analysis](https://onco.cc/key-papers/paper-pettersson-tmprss2-erg-outcome-meta-analysis-cebp-2012/), [Whole-genome and transcriptome sequencing of prostate cancer identifies new genetic alterations driving disease progression](https://onco.cc/key-papers/paper-ren-chinese-prostate-whole-genome-eur-urol-2018/)
- biomarkers: [AR amplification (gene and upstream enhancer)](https://onco.cc/biomarkers/ar-amplification/), [AR ligand-binding-domain mutation (L702H, W742C, H875Y, T878A, F877L)](https://onco.cc/biomarkers/ar-ligand-binding-domain-mutation/), [SPOP mutation](https://onco.cc/biomarkers/spop-mutation/), [TMPRSS2-ERG fusion (and the other ETS rearrangements)](https://onco.cc/biomarkers/tmprss2-erg-fusion/), [Treatment-emergent neuroendocrine transformation (recognising it)](https://onco.cc/biomarkers/nepc-transformation/)
- pairings: [PARP inhibitor + AR pathway inhibitor (prostate)](https://onco.cc/pairings/parp-plus-arpi/)
- ideas: [Design drug pairs where resisting one makes you vulnerable to the other](https://onco.cc/ideas/idea-bio1-evolutionary-double-bind/), [Destroy the truncated androgen receptor that hormone drugs cannot touch](https://onco.cc/ideas/idea-bio1-arv7-degrader/)
- pathways: [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [Prostate cancer (KEGG map)](https://onco.cc/pathways/prostate-cancer-signalling/), [RNA splicing](https://onco.cc/pathways/rna-splicing/), [Transcriptional machinery & addiction](https://onco.cc/pathways/transcription-addiction/)

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