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 R. 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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Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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