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Type: Journal article
Title: The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer
Author: Hickey, T.E.
Selth, L.A.
Chia, K.M.
Laven-Law, G.
Milioli, H.H.
Roden, D.
Jindal, S.
Hui, M.
Finlay-Schultz, J.
Ebrahimie, E.
Birrell, S.N.
Stelloo, S.
Iggo, R.
Alexandrou, S.
Caldon, C.E.
Abdel-Fatah, T.M.
Ellis, I.O.
Zwart, W.
Palmieri, C.
Sartorius, C.A.
et al.
Citation: Nature Medicine, 2021; 27(2):310-320
Publisher: Nature Research
Issue Date: 2021
ISSN: 1078-8956
Statement of
Theresa E. Hickey, Luke A. Selth, Kee Ming Chia, Geraldine Laven-Law, Heloisa H. Milioli, Daniel Roden ... et al.
Abstract: The 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.
Keywords: Cell Line, Tumor
Breast Neoplasms
Receptors, Androgen
Estrogen Receptor alpha
Signal Transduction
Cell Proliferation
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Nuclear Receptor Coactivator 3
MCF-7 Cells
Rights: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41591-020-01168-7
Published version:
Appears in Collections:Aurora harvest 8
Biochemistry publications

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