Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Xenografting of advanced stage breast cancer preserves the genomic and clonal architecture and captures luminal tumors harboring mutations and gene rearrangements in ESR1

ABSTRACT: End-stage breast cancers are clonally heterogeneous and harbor many poorly-understood treatment resistance mechanisms. We therefore established multiple Patient-Derived-Xenograft (PDX) models to study genomic events driving advanced disease. Comparative whole-genome sequencing of paired primary tumors and their PDX models demonstrated that PDX retain the vast majority of the structural variations and copy number aberrations seen within the originating tumor, and with high fidelity. Variant allele fractions (VAF) were preserved, even for rare mutations. Clonal representation is therefore a transplantable phenotype, indicating that genomic heterogeneity can be regulated in a tumor-autonomous mechanism, indifferent to host immune status. Mutations and gene rearrangements were documented in the ESR1 gene in three of five sequenced luminal PDX/progenitor tumor pairs (amplification, point mutation and translocation), and were associated with clinical endocrine response phenotypes, differential PDX estradiol responsiveness and all induced estradiol-independent growth in standard cell lines. PDX models are therefore a significant new tool for fundamental studies on the molecular basis for resistance to endocrine treatment in advanced breast cancer. reference x sample

ORGANISM(S): Homo sapiens

SUBMITTER: Charles Perou

PROVIDER: E-GEOD-46604 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Li Shunqiang S Shen Dong D Shao Jieya J Crowder Robert R Liu Wenbin W Prat Aleix A He Xiaping X Liu Shuying S Hoog Jeremy J Lu Charles C Ding Li L Griffith Obi L OL Miller Christopher C Larson Dave D Fulton Robert S RS Harrison Michelle M Mooney Tom T McMichael Joshua F JF Luo Jingqin J Tao Yu Y Goncalves Rodrigo R Schlosberg Christopher C Hiken Jeffrey F JF Saied Laila L Sanchez Cesar C Giuntoli Therese T Bumb Caroline C Cooper Crystal C Kitchens Robert T RT Lin Austin A Phommaly Chanpheng C Davies Sherri R SR Zhang Jin J Kavuri Megha Shyam MS McEachern Donna D Dong Yi Yu YY Ma Cynthia C Pluard Timothy T Naughton Michael M Bose Ron R Suresh Rama R McDowell Reida R Michel Loren L Aft Rebecca R Gillanders William W DeSchryver Katherine K Wilson Richard K RK Wang Shaomeng S Mills Gordon B GB Gonzalez-Angulo Ana A Edwards John R JR Maher Christopher C Perou Charles M CM Mardis Elaine R ER Ellis Matthew J MJ

Cell reports 20130919 6

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, demo ...[more]

PMID: 24055055

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Project description:Introduction: Over the past several years, we have been interested in understanding the mechanisms by which hormone-dependent (HD) mammary carcinomas grow in the absence of the stimulatory hormone. We have hypothesized that the stromal compartment plays a pivotal role in the acquisition of the hormone-independent (HI) phenotype by providing stimulatory factors that replace the proliferative effects of the hormone. Methods: We used DNA microarrays to compare the gene expression profiles of tumors from the MPA mouse breast cancer model, one hormone-dependent (C4-HD) and one hormone-independent (C4-HI), using whole tumor samples or laser-captured purified stromal and epithelial cells obtained from the same tumors. The expression of selected genes was validated by immunohistochemistry and immunofluorescence assays. Results: We identified 413 genes that were expressed in tumor stroma but not in epithelial cells. Eighty-five percent of these genes were upregulated, whereas the remaining 15% were downregulated in C4-HI tumors relative to their expression in the C4-HD tumor stroma. Several matrix metallopeptidases, including Mmp13, Mmp3, Mmp10 and Mmp9, were overexpressed in the C4-HI tumor microenvironment. On the other hand, 1100 genes were specifically expressed in the tumor parenchyma. Among them, the 29% were upregulated, whereas the remaining 71% were downregulated, in C4-HI relative to C4-HD tumor epithelium. Steap, Pdgfc, Runx2, Cxcl9 and Sdf2 were among the genes with high expression in the C4-HI tumor parenchyma. Interestingly, we found that Fgf2 was one of the few genes upregulated by MPA in C4-HD tumors, confirming its pivotal role in regulating tumor growth in this model. Conclusions: We demonstrate a gene expression profile that distinguishes epithelial from stromal cells in mammary tumors with different hormone dependence. Our results support the hypothesis that the tumor-associated stroma may contribute to hormone-independent tumor growth. The fact that Fgf2 was one of these few stimulatory genes is worth investigating. reference X sample

Dataset Information

Xenografting of advanced stage breast cancer preserves the genomic and clonal architecture and captures luminal tumors harboring mutations and gene rearrangements in ESR1

Publications

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

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