Cell Reports
Volume 4, Issue 6, 26 September 2013, Pages 1116-1130
Journal home page for Cell Reports

Article
Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts

https://doi.org/10.1016/j.celrep.2013.08.022Get rights and content
Under a Creative Commons license
open access

Highlights

  • Genome-wide structural variants are highly preserved in breast cancer PDX models

  • PDXs harbor rarely functionally significant single-nucleotide variants

  • PDXs harbor ESR1 mutations and translocations associated with endocrine therapy resistance

  • ESR1 gene amplification in PDX correlated with paradoxical estradiol-induced regression

Summary

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.

Cited by (0)

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

13

These authors contributed equally to this work