Estrogen-independent Myc overexpression confers endocrine therapy resistance on breast cancer cells expressing ER?Y537S and ER?D538G mutations.

ABSTRACT: Approximately 30% of metastatic breast cancers harbor estrogen receptor ? (ER?) mutations associated with resistance to endocrine therapy and reduced survival. Consistent with their constitutive proliferation, T47D and MCF7 cells in which wild-type ER? is replaced by the most common mutations, ER?Y537S and ER?D538G, 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 ER?D538G breast tumors, ER?Y537S tumors exhibited a dramatic increase in lung metastasis. Transcriptome analysis showed that the ER?Y537S and ER?D538G 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 ER? 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 ER? mutations.

SUBMITTER: Yu L 

PROVIDER: S-EPMC6351074 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature