PLX030482

GSE108304: Transcriptome Analysis Reveals a Role for Myc in Constitutive and Antiestrogen-resistant Proliferation of Breast Cancer Cells Expressing ERY537S and ERD538G Mutations

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Approximately 30% of metastatic breast cancers harbor estrogen receptor (ER/ESR1) mutations that are associated with resistance to endocrine therapy and shorter patient survival. How these ER 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 ER mutations, ERY537S and ERD538G. Here we use transcriptome analysis to demonstrate that ERY537S 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 ERY537S and ERD538G mutations. Notably, the T47DERY537S (TYS) cells exhibit a markedly different phenotype and transcriptome than the parental T47D cells and T47DERD538G (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 ERY537S and ERD538G 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 ER mutations and provides powerful tools for identifying pathways that contribute to the ER mutant phenotype. SOURCE: David,J,Shapiro (djshapir@life.illinois.edu) - University of Illinois Urbana-Champaign