Abstract 3275: Molecular characterization of human breast cancer xenografts reveals a strong genomic and gene expression stability
Authors: Reyal Fabien , Guyader Charlotte , Decraene Charles , Lucchesi Carlo , Auger Nathalie , Assayag Franck , DePlater Ludmilla , Gentien David , Poupon Marie-France , Cottu Paul , Cremoux Patricia De , Vincent-Salomon Anne , Roman-Roman Sergio , Delattre Olivier , Decaudin Didier , Marangoni Elisabetta 
Published: February 2011

Abstract
Introduction: Identifying new therapeutic agents for breast cancer (BC) treatment requires preclinical models that recapitulate the molecular characteristics of their respective clinical tumors. In this work, we analyzed the genomic and expression profiles of human breast cancer xenografts and their corresponding patient's tumors. Experimental Design:18 breast cancer xenografts (2 HER2 positive, 6 estrogen receptor positive (ER+), and 10 triple-negative) were obtained by grafting tumor fragments from patients into Swiss nude mice. The molecular characterization of patient's and xenograft's tumors was performed by DNA copy number analysis using a home-made BAC array (aCGH) as well as gene expression profiling using Affymetrix HGU133 Plus 2.0 Microarrays. Results : We compared the genomic profiles of BC xenografts with those of respective patient's donor tumors by calculating the correlation coefficient based on the status of the probes on each pair of chromosomes. We found that 14/18 paired tumors (78%) had a correlation coefficient higher than 0.50 [range 0.18-0.85]. aCGH based unsupervised hierarchical clustering analysis showed that 16/18 pairs segregated together and revealed the presence of the different molecular classes (ER+, triple negative and HER2+). We next analyzed the gene expression profile of the paired primary tumors and xenografts and identified that both ESR1 and HER2 gene expression, as well as gene expression profiles as described in molecular subtype's classification, showed no or few variations. However, using a linear regression analysis model we identified 558 Probesets corresponding to 371 unique genes differentially expressed in more than 84% of paired tumors, of which 536 were under-expressed and 22 over-expressed in the xenografts. Immune response, response to wounding, extracellular matrix component, cell adhesion, and angiogenesis constituted the main categories thus identified. An exploratory analysis in a large public dataset of 1143 breast cancer samples evaluated the prognostic value of the 558 Probe Sets and showed a highly significant enrichment in genes with prognostic ability. The underexpression of human stromal compartment related genes in the xenografts may highlight its involvement in the prognosis of breast cancer patients.
Finally, further analyses on xenografts at sequential tumor passages did not reveal important changes in the genomic rearrangements, neither in the gene expression profiles. These data suggest a striking genetic stability of the models across the time. Conclusions: This panel of human BC xenografts accurately maintains the genomic and the expression profiles of their corresponding patient's tumors and are stable across sequential in vivo passages. Consequently, these xenografts encompassing all breast cancer subtypes represent an ideal model for preclinical investigation of new therapeutic agents.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3275.