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| Status |
Public on Dec 31, 2017 |
| Title |
T47D xenografts treated with various combinations of ER- and PR-targeting therapies |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
|
| Summary |
Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and importantly, PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. This better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher anti-tumor activity of combination therapies of tamoxifen with PR antagonists and modulators. The study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist) from unique isoform and ligand-specific effects will guide the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic.
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| Overall design |
For the xenograft studies involving PR agonists (progesterone, MPA and R5020), PR antagonists (CDB4124, CDB4453 and EC313) and SERMs (tamoxifen, raloxifene, bazedoxifene and fulvestrant), mice harboring T47D xenografts were injected intra-peritoneal for three weeks with 10 mg/kg/day of the respective drugs. Five injections per week were administered. At the end of the duration of the experiment, mice were sacrificed; tumors were excised, weighed, fixed and snap-frozen for later analyses. RNA-seq was performed on these harvested xenografts.
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| Citation(s) |
29435103 |
| Submission date |
Apr 25, 2016 |
| Last update date |
May 23, 2019 |
| Contact name |
Hari Singhal |
| E-mail(s) |
hari_singhal@dfci.harvard.edu
|
| Organization name |
University of Chicago
|
| Department |
Ben May Department for Cancer Research
|
| Lab |
Geoffrey L Greene
|
| Street address |
929 E 57th St
|
| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60637 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (17)
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| This SubSeries is part of SuperSeries: |
| GSE80620 |
Progesterone Receptor Isoforms, Agonists and Antagonists Differentially Reprogram Estrogen Signaling. |
|
| Relations |
| BioProject |
PRJNA319523 |
| SRA |
SRP074150 |
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