Despite the promise of the cancer stem cell (CSC) model, its clinical relevance remains to be proven in breast cancer (BC) and requires a sensitive xenograft assay to define CSC on key functional properties i.e tumorigenicity, self-renewal and differentiation potential.
We report the establishment of primary breast tumor-derived xenografts (PDXs) that retain main primary tumors features (histo-phenotypic, molecular and genomic features, hierarchical organization of the tumoral cell population). We demonstrate that success in engraftment is correlated with the presence of CSC in primary tumor and predicts prognosis in patients (HR= 3.61; 95%CI [1.12-11.65], p=3.20E-02).
The xenograft assay demonstrated the hierarchical organization of BC. Analysis of gene expression from functionally validated CSC yield to a breast CSC signature (BCSC-GES) is an independent predictor of patient survival. We then identified a core of genes commonly expressed by BCSC and embryonic, hematopoietic, neural stem cells, the CE-4SC. This shared transcriptional program comprised 19 genes encoding mismatch and nucleotide excision repair proteins, proteins implicated in transport through the endoplasmic reticulum, RNA processing, translation and transcriptional regulators, enzymes of detoxification and mitochondrial/oxidative stress, or enzymes of lipid metabolism. This “universal” stem cell program is also an independent predictor of patient survival.
Using a screening of an RNA-interference library specially designed to block the expression of these 19 target genes, we validated the effect of single gene knock-down (KD) on the breast CSC population for 14 genes (KD of 5 genes decreased the CSC population and were called “self-renewers”genes, KD of 9 genes increased the CSC, and were designated as“differentiators”).
Hence, this study validated the clinical relevance of CSC model in breast cancer for the first time, and the ability of PDXs to accelerate transfer for personalized CSC therapy into clinics.
Citation Format: Emmanuelle Charafe-Jauffret, Christophe Ginestier, Francois Bertucci, Olivier Cabaud, Jose Adelaide, Max Chaffanet, Luc Xerri, Patrice Viens, Daniel Birnbaum. Cancer stem cells predict engraftment and poor prognosis of primary breast tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 244. doi:10.1158/1538-7445.AM2013-244