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| Status |
Public on Feb 07, 2019 |
| Title |
Transcriptome Analysis Reveals a Role for Myc in Constitutive and Antiestrogen-resistant Proliferation of Breast Cancer Cells Expressing ERαY537S and ERαD538G Mutations |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Approximately 30% of metastatic breast cancers harbor estrogen receptor α (ERα/ESR1) mutations that are associated with resistance to endocrine therapy and shorter patient survival. How these ERα mutations elicit an aggressive tumor phenotype was largely unknown. Recently, we reported cell lines in which the wild-type ESR1 gene is replaced by the two most common ERα mutations, ERαY537S and ERαD538G. Here we use transcriptome analysis to demonstrate that ERαY537S cells exhibit a unique expression profile and phenotype, and identify an important role for Myc in the increased growth rate, ligand independent cell proliferation, and partial resistance to tamoxifen and fulvestrant of cells expressing the ERαY537S and ERαD538G mutations. Notably, the T47DERαY537S (TYS) cells exhibit a markedly different phenotype and transcriptome than the parental T47D cells and T47DERαD538G (TDG) cells. Consistent with their estrogen-independent proliferation, RNAseq shows the TYS and TDG cells exhibit estrogen independent gene expression patterns. Gene set enrichment analysis showed Myc target pathways are highly induced in both mutant cell lines. Unlike the parental T47D cells, in TYS and TDG cells Myc mRNA and protein exhibit constitutive, fulevestrant-resistant expression. Moreover, chromatin immunoprecipitation (ChIP) showed that ERαY537S and ERαD538G exhibit constitutive, fulvestrant-resistant, recruitment to the Myc enhancer region. Myc knockdown showed that Myc protein is required for ligand independent proliferation of TYS and TDG cells. Constitutive MYC expression in T47D cells, to levels similar to those in TYS and TDG cells, partially recapitulated the aggressive phenotypes of the TYS and TDG cells. Our study demonstrates a previously undescribed role for constitutive and antiestrogen resistant Myc expression in the aggressive phenotype exhibited by breast cancer cells expressing ERα mutations and provides powerful tools for identifying pathways that contribute to the ERα mutant phenotype.
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| Overall design |
Hormone depleted T47D, TYS and TDG cells were treated with 10nM E2 or ethanol, as vehicle control, for 4 hours or 24 hours with 3 biological replicates. RNAseq was carried out using Illumina Hiseq 4000.
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| Contributor(s) |
Yu L, Shapiro D |
| Citation(s) |
30419347 |
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| Submission date |
Dec 19, 2017 |
| Last update date |
Mar 21, 2019 |
| Contact name |
David J Shapiro |
| E-mail(s) |
djshapir@life.illinois.edu
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| Organization name |
University of Illinois Urbana-Champaign
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| Department |
Biochemistry
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| Street address |
600 South Mathews Avenue
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| City |
Urbana |
| State/province |
IL |
| ZIP/Postal code |
61801 |
| Country |
USA |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (27)
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| Relations |
| BioProject |
PRJNA423078 |
| SRA |
SRP127181 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE108304_RAW.tar |
80.8 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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