UC San Diego

Parallels between stem cells, development and cancer have long been recognized, but few molecular links have been delineated. Here, we identify and characterize a population of fetal mammary stem cells (fMaSCs). fMaSC concentration peaked late in fetal development well after the emergence of the earliest mammary structures. Several characteristics of fMaSCs enabled more extensive purification than previously achieved using adult mammary. Single cells from the fMaSC-enriched population generated multi-lineage spheres. These cells also revealed properties often associated with cancers. For example, we observed cells co-expressing luminal, myoepithelial and mesenchymal markers. Gene expression profiling revealed significant similarities with archived breast cancer arrays. The ErbB Pathway was heavily represented and fMaSC derived spheres were sensitive to ErbB kinase inhibition. The fMaSC expression profile was associated with aggressive breast cancer subtypes and consisted of unique gene modules with relevance for prognosis and the potential to indicate new therapeutic targets. The parallels between development and cancer suggest that close relationships may exist between organ specific fetal stem cells and cancer. Here, we overcome the substantial technical challenges of such studies to identify, isolate and characterize fetal mammary stem cells (fMaSCs). We report the surprising finding that fMaSC activity is rare early and undergoes a significant increase late in fetal mammogenesis when the rudiments invade into the mesenchyme and fat pad. We find that regulatory pathways associated with fMaSCs are also differentially expressed in a subset of human breast cancers, suggesting that cancer cells may evolve to recapitulate the fetal stem cell state. Our characterization of the fetal mammary stem cell state provides a resource for generating new molecular hypotheses linking development and cancer, identifying candidate therapeutic targets, and developing new diagnostic and prognostic metrics