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| Status |
Public on Jan 18, 2021 |
| Title |
The Androgen Receptor is a Tumor Suppressor in Estrogen Receptor Positive Breast Cancer [ZR-75-1 cell line Bicalutamide study ER ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
The role of the androgen receptor (AR) in estrogen receptor alpha (ER) 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 anti-tumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Importantly, 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 up-regulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER+ breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER+ breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.
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| Overall design |
ChIP-seq for ERα in ZR-75-1 cells cultured in steroid-depleted conditions and treated for 6 hours with Vehicle, 1 nM E2, 1 µM Bicalutamide, E2 + Bicalutamide, or E2 + 1 nM DHT. Bicalutamide was added 1 h prior to any hormone addition.
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| Contributor(s) |
Hickey TE, Selth LA, Laven-Law G, Ebrahimie E, Tilley WD |
| Citation(s) |
33462444 |
| Submission date |
Dec 06, 2019 |
| Last update date |
Jan 26, 2021 |
| Contact name |
Luke Selth |
| E-mail(s) |
luke.selth@flinders.edu.au
|
| Organization name |
Flinders University
|
| Department |
College of Medicine and Public Health
|
| Street address |
Flinders Drive
|
| City |
Bedford Park |
| State/province |
SA |
| ZIP/Postal code |
5042 |
| Country |
Australia |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE123770 |
The Androgen Receptor is a Tumor Suppressor in Estrogen Receptor Positive Breast Cancer |
|
| Relations |
| BioProject |
PRJNA594007 |
| SRA |
SRP234985 |
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