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| Status |
Public on Jan 18, 2021 |
| Title |
The Androgen Receptor is a Tumor Suppressor in Estrogen Receptor Positive Breast Cancer [PDX model HCI-005 ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| 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 AR, ERĪ±, and H3K27ac in the patient-derived xenograft (PDX) tumor model HCI-005 treated for 5 days with either Vehicle, DHT, or Enobosarm.
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| Contributor(s) |
Hickey TE, Selth LA, Chia KM, Milioli HH, Roden D, Laven-Law G, Lim W, Tilley WD |
| Citation(s) |
33462444 |
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| Submission date |
Apr 17, 2019 |
| Last update date |
Jan 26, 2021 |
| Contact name |
Luke Selth |
| E-mail(s) |
luke.selth@flinders.edu.au
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| Organization name |
Flinders University
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| Department |
College of Medicine and Public Health
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| Street address |
Flinders Drive
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| City |
Bedford Park |
| State/province |
SA |
| ZIP/Postal code |
5042 |
| Country |
Australia |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (10)
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| This SubSeries is part of SuperSeries: |
| GSE123770 |
The Androgen Receptor is a Tumor Suppressor in Estrogen Receptor Positive Breast Cancer |
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| Relations |
| BioProject |
PRJNA533223 |
| SRA |
SRP192819 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE129930_RAW.tar |
10.0 Gb |
(http)(custom) |
TAR (of BED, BIGWIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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