Hickey, Theresa E, Selth, Luke A, Chia, Kee Ming, Laven-Law, Geraldine, Milioli, Heloisa H, Roden, Daniel, Jindal, Shalini, Hui, Mun, Finlay-Schultz, Jessica, Ebrahimie, Esmaeil et al (show 14 more authors)
(2021)
The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer.
NATURE MEDICINE, 27 (2).
310-+.
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Hickey et al. 2021.pdf - Author Accepted Manuscript Download (113MB) | Preview |
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Cell Line, Tumor, Humans, Breast Neoplasms, Receptors, Androgen, Estrogen Receptor alpha, Androgens, Signal Transduction, Cell Proliferation, Female, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Nuclear Receptor Coactivator 3, MCF-7 Cells |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 11 Feb 2021 10:10 |
| Last Modified: | 24 Mar 2023 12:20 |
| DOI: | 10.1038/s41591-020-01168-7 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3115480 |
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