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

By Shunqiang Li, D. Shen, Jieya Shao, R. Crowder, Wenbin Liu, Aleix Prat, Xiaping He, Shuying Liu, J. Hoog, Charles Lu and 45 more. Cell Reports, 2013

626 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6a960d240685fcc6fe0c9678c53e84299df0eac9

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Citations in the corpus

Overcoming Endocrine Resistance in Breast Cancer (2020, positive): “Stable ESR1 in-frame gene fusions were first reported in 2013 (Li et al., 2013) and have since been found in at least 1% of MBCs (usually in tumors resistant to endocrine therapy) (Hartmaier et al.”
Signal transduction in cancer. (2015, neutral): “Disruption of the balance between ERa and ERb or mutations in ERa that yield truncated proteins or activated proteins can dysregulate this pathway (Thomas and Gustafsson 2011; Li et al. 2013; Robinson et al. 2013; Toy et al. 2013).”
Subclonal diversification of primary breast cancer revealed by multiregion sequencing (2015, positive): “Genome sequencing has enabled analysis of clonal evolution in breast cancer through sequencing of primary tumor and metastasis pairs in a few cases 4,5 , sequencing of single cells 2,6 and xenograft models 7 as well as deep sequencing for subclonal mutations 1,3 .”
Dynamics of genomic clones in breast cancer patient xenografts at single cell resolution (2014, neutral): “Cluster (n) 1 (60) 2 (23) 3 (15) 4 (14) 5 (13) 6 (11) 7 (9) 8 (6) 9 (5) 10 (5) 11 (3) 12 (3) 13 (2) 14 (2)”
The Hippo Signaling Pathway in Development and Disease (2019, background): “, 2011), luminal breast cancer (Li et al., 2013), and ependymoma (Pajtler et al.”