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

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.

• Authors: Shunqiang Li, Dong Shen, Jieya Shao, Robert Crowder, Wenbin Liu, Aleix Prat, Xiaping He, Shuying Liu, Jeremy Hoog, Charles Lu, Li Ding, Obi L Griffith, Christopher Miller, Dave Larson, Robert S Fulton, Michelle Harrison, Tom Mooney, Joshua F McMichael, Jingqin Luo, Yu Tao, Rodrigo Goncalves, Christopher Schlosberg, Jeffrey F Hiken, Laila Saied, Cesar Sanchez, Therese Giuntoli, Caroline Bumb, Crystal Cooper, Robert T Kitchens, Austin Lin, Chanpheng Phommaly, Sherri R Davies, Jin Zhang, Megha Shyam Kavuri, Donna McEachern, Yi Yu Dong, Cynthia Ma, Timothy Pluard, Michael Naughton, Ron Bose, Rama Suresh, Reida McDowell, Loren Michel, Rebecca Aft, William Gillanders, Katherine DeSchryver, Richard K Wilson, Shaomeng Wang, Gordon B Mills, Ana Gonzalez-Angulo, John R Edwards, Christopher Maher, Charles M Perou, Elaine R Mardis, Matthew J Ellis
• Journal: Cell reports (Cell Rep) Vol. 4 Issue 6 Pg. 1116-30 (Sep 26 2013) ISSN: 2211-1247 [Electronic] United States
• PMID: 24055055 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• ESR1 protein, human
• Estrogen Receptor alpha
• Neoplasm Proteins
• Phosphoproteins
• RNA, Neoplasm
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• Estradiol

Topics

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