Abstract 3000: Molecular profiling of residual tumor cells after various chemotherapies shows distinct gene expression patterns in patient-derived breast cancer xenografts
Authors: Gentien David , Depil Stéphane , Gestraud Pierre , Decraene Charles , Jules-Clement Gérôme , Albaud Benoit , Vincent-Salomon Anne , Reyal Fabien , Thuleau Aurélie , Cruzalegui Francisco , Tucker Gordon C. , Dubois Thierry , Roman-Roman Sergio , Decaudin Didier , Marangoni Elisabetta 
Published: August 2012

Abstract
Introduction: Triple negative breast cancer (TNBC) is an aggressive disease associated with a high risk of distant recurrence, rapid progression to death and poor overall survival. Systemic treatments of TNBC patients are limited to cytotoxic chemotherapy due to the lack of identified molecular targets. Therefore, the characterization of tumor cells that are responsible for recurrences after such treatments is of high therapeutic relevance. Using patient-derived TNBC xenografts that reproduce tumor relapse, we have analyzed the gene expression profile of residual cancer cells (RCC) after various chemotherapeutic treatments. Experimental design: Sixteen human breast cancer xenografts (HBCx) were treated with adriamycin-cyclophosphamide (AC), docetaxel, cisplatin, or capecitabine. Xenografts showing complete tumor remission followed by local relapse in at least 75% of mice were considered as tumor recurrence models. Gene expression profiles were obtained from tumor samples before treatment (untreated group) and after treatment (tumor remission and tumor recurrence groups) using Affymetrix U133 Gene Arrays. Results: Two xenograft models showed complete tumor remission after chemotherapy, i.e. the HBCx-10 xenograft (AC) and the HBCx-33 xenograft (cisplatin and capecitabine). An exploratory analysis on expression datasets of these xenografts tumors showed two distinct groups: one consisted of untreated and relapsed tumors and the other of RCC. The differential analysis showed no difference in gene expression between the untreated and relapsed tumors in the 2 models analyzed, whatever the cytotoxic agent administered. In contrast, when gene expression was analyzed in RCC compared to untreated or relapsed tumors, we found 2405 genes differentially expressed in the HBCx-10 xenograft (fold change greater than 2 or less than −2), and 2886 and 945 genes in the HBCx-33 one treated with capecitabine and cisplatin, respectively. By comparing the 3 lists of differentially expressed genes, we found 227 common genes, 137 being up-regulated and 90 down-regulated. Gene Ontology analysis of these genes revealed enrichment in several biological processes related to immune response, response to wounding, inflammatory response, cell proliferation, cell adhesion, and apoptosis. Validation studies with additional RNA and protein studies are currently ongoing on selected deregulated genes. Conclusions This study supports the existence of a distinct molecular profile of residual tumor cells after chemotherapy in TNBC, with a subset of deregulated genes common to the different tumors analyzed and the different administered treatments. Further elucidation of the signaling pathways associated to these deregulated genes may provide key insights into the molecular mechanism driving breast cancer recurrence.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3000. doi:1538-7445.AM2012-3000