Abstract 4423: Molecular characterization of cell foci that escape chemotherapy in relapsing models of human breast tumorgraft
Authors: Marie-Emmanuelle Legrier, Arnaud Beurdeley, Olivier Deas, Myriam Lassalle, Marie-France Poupon, Stefano Cairo, Jean-Gabriel Judde
Journal: Cancer Research (2011)

Abstract Despite great efforts in the field during the last decade, the genetic basis of cancer progression remains unknown. Most of treatments currently available fail in providing complete tumor eradication. This incomplete efficacy frequently exposes patients at risk of recurrence. Therefore, it is important to investigate the molecular basis of tumor resistance to treatment and to identify genes or pathways to be targeted to improve the efficacy of therapeutic intervention. The heterogeneous nature of cancer makes this identification difficult. This research project proposes to characterize the molecular profile of residual tumor cells responsible for relapse following chemotherapy-induced tumor regression in a panel of human breast cancer xenografts. From a panel of human breast cancer xenografts established in mouse from patient tumors, 3 tumorgraft models that undergo macroscopic complete regression by chemotherapy, followed by tumor recurrence after an average period of 30 days, were selected for this study. For each model, residual cell nodules that survived chemotherapy-induced tumor regression were identified by histological analysis. Laser-capture microdissection and RNA extraction were performed on samples from parental tumors prior to treatment, residual foci and recurrent tumors. Transcriptome analysis and microRNA (miRNA) profiling were assessed. Unsupervised analysis of gene and miRNA expression in parental, residual tumor and recurrent tumor cells of each model clearly showed that the overall molecular phenotype of the residual cells as well as of the relapsed tumor was not affected by the treatment. Samples derived from the same tumor model preferentially cluster with each other instead of forming a condition-related group. However, by comparative analysis with untreated samples, the resistant cell foci showed alteration of several genes and pathways that probably mediate cell response to the drug-induced stress. Part of these alterations are transient, as they disappear in the relapsing tumor, whereas as few of them seem to keep a certain degree of alteration, suggestive of a treatment-derived “fingerprint”. Further in silico and functional validation studies will be performed to identify the key pathways implicated in cells resistant to chemotherapy. These pathways will be selectively targeted in combination with conventional chemotherapy in order to try to achieve complete eradication of the tumor. This study shows the importace of the xenograft models of human cancer for in vivo functional studies, and indicates the use of these panels as a preferential option for the exploration and improvement of anti-cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4423. doi:10.1158/1538-7445.AM2011-4423