Estrogen-independent Myc overexpression confers endocrine therapy resistance on breast cancer cells expressing ERαY537S and ERαD538G mutations

Liqun Yu, Lawrence Wang, Chengjian Mao, Darjan Duraki, Ji Eun Kim, Rui Huang, William G Helferich, Erik Nelson, Ben Ho Park, David J Shapiro

Research output: Contribution to journalArticle

Abstract

Approximately 30% of metastatic breast cancers harbor estrogen receptor α (ERα) mutations associated with resistance to endocrine therapy and reduced survival. Consistent with their constitutive proliferation, T47D and MCF7 cells in which wild-type ERα is replaced by the most common mutations, ERαY537S and ERαD538G, exhibit partially estrogen-independent gene expression. A novel invasion/dissociation/rebinding assay demonstrated that the mutant cells have a higher tendency to dissociate from invasion sites and rebind to a second site. Compared to ERαD538G breast tumors, ERαY537S tumors exhibited a dramatic increase in lung metastasis. Transcriptome analysis showed that the ERαY537S and ERαD538G mutations each elicit a unique gene expression profile. Gene set enrichment analysis showed Myc target pathways are highly induced in mutant cells. Moreover, chromatin immunoprecipitation showed constitutive, fulvestrant-resistant, recruitment of ERα mutants to the Myc enhancer region, resulting in estrogen-independent Myc overexpression in mutant cells and tumors. Knockdown and virus transduction showed Myc is necessary and sufficient for ligand-independent proliferation of the mutant cells but had no effect on metastasis-related phenotypes. Thus, Myc plays a key role in aggressive proliferation-related phenotypes exhibited by breast cancer cells expressing ERα mutations.

Original languageEnglish (US)
Pages (from-to)373-382
Number of pages10
JournalCancer Letters
Volume442
DOIs
StatePublished - Feb 1 2019

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Estrogen Receptors
Estrogens
Breast Neoplasms
Mutation
Neoplasm Metastasis
Phenotype
Chromatin Immunoprecipitation
MCF-7 Cells
Gene Expression Profiling
Therapeutics
Transcriptome
Neoplasms
Cell Proliferation
Ligands
Viruses
Gene Expression
Lung
Genes

Keywords

  • Breast cancer
  • ERαD538G
  • ERαY537S
  • Metastasis
  • Myc
  • RNAseq

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Estrogen-independent Myc overexpression confers endocrine therapy resistance on breast cancer cells expressing ERαY537S and ERαD538G mutations. / Yu, Liqun; Wang, Lawrence; Mao, Chengjian; Duraki, Darjan; Kim, Ji Eun; Huang, Rui; Helferich, William G; Nelson, Erik; Park, Ben Ho; Shapiro, David J.

In: Cancer Letters, Vol. 442, 01.02.2019, p. 373-382.

Research output: Contribution to journalArticle

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abstract = "Approximately 30{\%} of metastatic breast cancers harbor estrogen receptor α (ERα) mutations associated with resistance to endocrine therapy and reduced survival. Consistent with their constitutive proliferation, T47D and MCF7 cells in which wild-type ERα is replaced by the most common mutations, ERαY537S and ERαD538G, exhibit partially estrogen-independent gene expression. A novel invasion/dissociation/rebinding assay demonstrated that the mutant cells have a higher tendency to dissociate from invasion sites and rebind to a second site. Compared to ERαD538G breast tumors, ERαY537S tumors exhibited a dramatic increase in lung metastasis. Transcriptome analysis showed that the ERαY537S and ERαD538G mutations each elicit a unique gene expression profile. Gene set enrichment analysis showed Myc target pathways are highly induced in mutant cells. Moreover, chromatin immunoprecipitation showed constitutive, fulvestrant-resistant, recruitment of ERα mutants to the Myc enhancer region, resulting in estrogen-independent Myc overexpression in mutant cells and tumors. Knockdown and virus transduction showed Myc is necessary and sufficient for ligand-independent proliferation of the mutant cells but had no effect on metastasis-related phenotypes. Thus, Myc plays a key role in aggressive proliferation-related phenotypes exhibited by breast cancer cells expressing ERα mutations.",
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AU - Kim, Ji Eun

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