Abstract 1015: Mammary stem cells increase late in embryogenesis, facilitating their characterization and revealing links to breast cancer

Parallels between embryonic development, stem cells, and cancer have long been recognized. The proliferative and invasive characteristics of the most lethal forms of breast cancer and their lack of differentiated characteristics resemble aspects of embryonic mammogenesis, raising the possibility that they share molecular mechanisms. We have identified, isolated and characterized a fetal mammary population with concentrated mammary stem cell activity and shown that it exhibits gene expression similarities to certain human breast cancer molecular subtypes. Limiting dilution transplantation analyses demonstrate that a robust increase in fetal mammary stem cell (fMaSC) activity is evident after embryonic day 16 (E16), coincident with invasion of the rudiment through the mesenchyme and into the fat pad precursor. Markers used to enrich adult MaSCs enabled isolation of a population at E18.5 that is highly enriched for fMaSCs and capable of serial transplantation in vivo and clonal, multilineage sphere formation in vitro. Genome-wide expression profiling and single cell analyses revealed candidate pathways in both the epithelial and stromal compartments with relevance to fMaSC activity and cancer. Notably, ErbB and FGF signaling were critical and synergistic for the in vitro growth of spheres derived from the fMaSC-enriched population, and fMaSCs expressed elevated ErbB2, 3, and 4 relative to adult MaSC enriched populations. We explored molecular links between fetal mammary development and cancer further by analyzing the expression of fetal gene signatures in archived breast cancer array data and in breast cancer cell lines. We identified gene expression modules correlating with certain cell lines, intrinsic breast cancer subtypes and clinical outcome. These studies advance the attractive hypothesis that regulatory pathways governing fMaSC function and embryonic mammogenesis that are deregulated in certain types of human cancer can be targeted in the development of new therapies and prognostic metrics. 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 1015. doi:1538-7445.AM2012-1015