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| Status |
Public on Jul 11, 2018 |
| Title |
Transcriptional properties of estrogen receptor fusion genes. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor positive (ER+) breast cancer but their role in disease pathogenesis remains unclear. Herein we examined multiple in-frame and out-of-frame ESR1 fusions and found that two, both identified in advanced endocrine treatment resistant disease, encoded stable and functional in-frame fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, the N-terminal, DNA binding and dimerization motifs encoded by exons 2-6 were fused to C terminal sequences from the partner gene. Functional properties included estrogen-independent growth, constitutive expression of ER target genes, anti-estrogen resistance, induction of cellular motility in vitro and the development of lung metastasis in vivo. Chromatin immunoprecipitation and RNA sequencing experiments showed both fusions uniquely activated a metastasis-associated transcriptional program. ESR1-e6>YAP1 and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, palbociclib, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.
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| Overall design |
HA-ChIP-seq and RNA-seq of stable T47D breast cancer cell lines expressing HA-tagged ESR1 constructs in hormone deprived media -/+ E2. HA-ChIP DNA from YFP-HA expressing cells was used as input.
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| |
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| Contributor(s) |
Ellis MJ, Lei JT |
| Citation(s) |
30089255 |
| |
| Submission date |
Jun 22, 2018 |
| Last update date |
Mar 27, 2019 |
| Contact name |
Jonathan Thomas Lei |
| E-mail(s) |
jlei@bcm.edu
|
| Organization name |
Baylor College of Medicine
|
| Department |
Medicine - Lester and Sue Smith Breast Center
|
| Lab |
Eric C. Chang Lab
|
| Street address |
1 Baylor Plaza
|
| City |
Houston |
| State/province |
TX |
| ZIP/Postal code |
77030 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
|
| Samples (15)
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| Relations |
| BioProject |
PRJNA477539 |
| SRA |
SRP151140 |
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