Details

Autor(en) / Beteiligte

• 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
• Birrell, Stephen N
• Stelloo, Suzan
• Iggo, Richard
• Alexandrou, Sarah
• Caldon, C Elizabeth
• Abdel-Fatah, Tarek M
• Ellis, Ian O
• Zwart, Wilbert
• Palmieri, Carlo
• Sartorius, Carol A
• Swarbrick, Alex
• Lim, Elgene
• Carroll, Jason S
• Tilley, Wayne D

Titel

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

Ist Teil von

• Nature medicine, 2021-02, Vol.27 (2), p.310-320

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2021

Link zum Volltext

Beschreibungen/Notizen

• 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.