Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts

Cell Rep. 2013 Sep 26;4(6):1116-30. doi: 10.1016/j.celrep.2013.08.022. Epub 2013 Sep 19.

Abstract

To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Alleles
  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Drug Resistance, Neoplasm
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / genetics*
  • Female
  • Gene Amplification
  • Genomic Instability
  • Heterografts
  • Humans
  • Mice
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Staging
  • Phosphoproteins / genetics
  • Point Mutation
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • Transcription Factors
  • Translocation, Genetic

Substances

  • Adaptor Proteins, Signal Transducing
  • Estrogen Receptor alpha
  • Neoplasm Proteins
  • Phosphoproteins
  • RNA, Neoplasm
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • estrogen receptor alpha, human
  • Estradiol

Associated data

  • GEO/GSE46604
  • GEO/GSM41685