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Cell Rep ; 4(6): 1116-30, 2013 Sep 26.
Article in English | MEDLINE | ID: mdl-24055055

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.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Estrogen Receptor alpha/genetics , Adaptor Proteins, Signal Transducing/genetics , Alleles , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Drug Resistance, Neoplasm , Estradiol/pharmacology , 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 , YAP-Signaling Proteins
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