Abstract 1959: Lgr5 marks an enriched population of fetal mammary stem cells

Abstract

Abstract Basal-like breast cancers have unique characteristics that may contribute to their particularly poor prognosis. These include a high degree of genomic instability, intra-tumor heterogeneity, and gene expression profiles similar to those of normal mammary stem cells. These characteristics may arise through the aberrant propagation of normal stem cells. Alternatively, mutations commonly found in this subtype may be the dominant determinant of tumor phenotype. In order to explore these possibilities, pure populations of stem cells need to be isolated and analyzed. Our lab has identified a population of fetal mammary stem cells (fMaSCs) in the mouse whose gene expression profiles show a striking enrichment for those of human basal tumors. When fMaSCs were targeted with a p53 mutation, commonly found in human basal cancer, a tumor arose within 5 weeks- the shortest latency we have observed from any cell type. This suggests that fMaSCs are particularly prone to tumorigenesis and may likely be a source of basal-like tumors in the adult. Mammary stem cell activity becomes detectable at a defined time in late embryonic development, peaks right before birth, diminishes rapidly at birth, and remains low in the adult. We have since identified Lgr5 to be highly expressed in fMaSCs at the peak of their stem cell activity. We have gone on to use it to isolate the most pure population of fMaSCs measured yet by in vitro means. When plated in 3D culture containing 2% matrigel, up to 50% of Lgr5-expressing fetal mammary cells formed correctly polarized mammospheres. Using three independent methods, we will determine how Lgr5 expression tracks with stem cell activity throughout development and use this marker to test for the persistence of fetal-like stem cells in the adult mammary gland. We will develop comprehensive gene expression profiles from Lgr5+ cells throughout development to identify molecular correlates of the stem cell state. The relative contributions of developmental state of cell of origin or mutational status to tumor phenotype are poorly understood. We will test the capacity of stem cells at various stages of development to give rise to tumors when targeted with mutations commonly found in human basal tumors. A thorough analysis of tumors will reveal links between development, tumor initiation and progression, and provide insight into strategies to treat basal breast cancers. Citation Format: Christy L. Trejo, Ben Spike, Geoff Wahl. Lgr5 marks an enriched population of fetal mammary stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1959. doi:10.1158/1538-7445.AM2014-1959