Abstract 5339: Breast cancer stem cells predict engraftment <i>in vivo</i> of primary tumor and are characterized by a gene expression signature associated with poor prognosis.
Authors: Emmanuelle Charafe-Jauffret, Christophe Ginestier, Francois Bertucci, Olivier Cabaud, Julien Wicinski, Pascal Finetti, Emmanuelle Josselin, Tien-Tuan N'guyen, Florence Monville, Jocelyne Jacquemier, Gilles Houvenaeghel, Luc Xerri, Patrice Viens, Daniel Birnbaum
Journal: Cancer Research (2012)

Abstract Development of pre-clinical models that reflect tumor biology and metastatic progression is a critical issue to better develop therapeutic strategies. The xenotransplantation mouse model of human primary tumors is presented as the best model to mimic patient tumor biology in different pathologies. In breast tumors, orthotopic transplantation recently provides strong evidence of maintenance in xenotransplants of main cognate breast tumoral features. As it has recently been reported that primary breast tumor engraftment is a prognostic indicator of disease outcome for women with breast cancer, we aimed to determine parameters that influence engraftment success. Between January 2008 and June 2009, we transplanted 76 fresh primary tumors from 76 different individuals into cleared and humanized fat pad of female NOD-SCID/ gamma (c) null mice. Tumors grew from 20 out of the 76 samples (29%), and we maintained the main molecular (molecular subtypes, genomic profiles, phenotypes) and histological features of matched primary tumors in xenografts. If a high grade, an absence of hormone receptor expression, a basal-like/ERBB2 molecular subtype was correlated with engrafment rate, the presence of ALDH-expressing CSC in primary tumors was the only parameter predicting engraftment in an independent manner. Using this model, we showed that breast cancer xenografts were hierarchically organized with a subpopulation of ALDEFLUOR-positive cells that maintains tumorigenic activity. In order to identify pathways regulating tumorigenic activity of the CSC population, we derived a CSC gene expression signature (GES) from the comparison of expression profiles of the ALDEFLUOR-positive and -negative populations from our xenograft series. This CSC signature presented three mains core transcriptional programs containing DNA repair genes, suggesting a special ability to resist to DNA damage, gene of G1-S transition checkpoint control including pRb and E2F, and gene of G2-M transition checkpoint, suggesting a potential role in self-renewal and differentiation programs. Given that the presence of CSC in primary tumors is an indicator of tumor engraftment and engraftment predict prognosis, we surmised that molecular machinery governing CSC properties is likely to influence clinical outcome. Indeed, our established CSC GES was able to predict bad outcome in primary breast cancer. Thus, we can speculate that the greater retention of cancer stem cell programs observed in patients with shorter survival compared with those with better outcome may reflect greater uncoupling of self-renewal and maturation programs. Overall, our data indicate the importance of developing CSC biomarkers to contribute to personalized cancer therapy and the need to identify therapeutic targets directed toward CSCs using orthotopic xenografts models. 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 5339. doi:1538-7445.AM2012-5339