The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer

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dc.contributor.authorHickey, T.E.
dc.contributor.authorSelth, L.A.
dc.contributor.authorChia, K.M.
dc.contributor.authorLaven-Law, G.
dc.contributor.authorMilioli, H.H.
dc.contributor.authorRoden, D.
dc.contributor.authorJindal, S.
dc.contributor.authorHui, M.
dc.contributor.authorFinlay-Schultz, J.
dc.contributor.authorEbrahimie, E.
dc.contributor.authorBirrell, S.N.
dc.contributor.authorStelloo, S.
dc.contributor.authorIggo, R.
dc.contributor.authorAlexandrou, S.
dc.contributor.authorCaldon, C.E.
dc.contributor.authorAbdel-Fatah, T.M.
dc.contributor.authorEllis, I.O.
dc.contributor.authorZwart, W.
dc.contributor.authorPalmieri, C.
dc.contributor.authorSartorius, C.A.
dc.contributor.authoret al.
dc.date.issued2021
dc.description.abstractThe role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.
dc.description.statementofresponsibilityTheresa E. Hickey, Luke A. Selth, Kee Ming Chia, Geraldine Laven-Law, Heloisa H. Milioli, Daniel Roden ... et al.
dc.identifier.citationNature Medicine, 2021; 27(2):310-320
dc.identifier.doi10.1038/s41591-020-01168-7
dc.identifier.issn1078-8956
dc.identifier.issn1546-170X
dc.identifier.orcidHickey, T.E. [0000-0002-2752-730X]
dc.identifier.orcidSelth, L.A. [0000-0002-4686-1418]
dc.identifier.orcidLaven-Law, G. [0000-0001-5326-1931]
dc.identifier.orcidBirrell, S.N. [0000-0002-1023-413X]
dc.identifier.orcidTilley, W.D. [0000-0003-1893-2626]
dc.identifier.urihttp://hdl.handle.net/2440/130850
dc.language.isoen
dc.publisherNature Research
dc.rights© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
dc.source.urihttps://doi.org/10.1038/s41591-020-01168-7
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectReceptors, Androgen
dc.subjectEstrogen Receptor alpha
dc.subjectAndrogens
dc.subjectSignal Transduction
dc.subjectCell Proliferation
dc.subjectFemale
dc.subjectCyclin-Dependent Kinase 4
dc.subjectCyclin-Dependent Kinase 6
dc.subjectNuclear Receptor Coactivator 3
dc.subjectMCF-7 Cells
dc.titleThe androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer
dc.typeJournal article
pubs.publication-statusPublished

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