Notch Ligand Delta-like 1 Dictates Mammary Stem Cell Activity in Normal Development and Breast Tumorigenesis

Abstract

Emerging studies in the field of cancer biology suggest that cancer cells exhibit many characteristics shared by normal stem cells, including the ability to selfrenew and produce differentiated progeny. Subsequently, novel paradigms are being developed in light of the surmounting evidence that breast cancer tumors may originate from cancer stem cells, which in turn are derived from normal mammary stem cells (MaSCs). Currently in the field, accurate characterization of normal MaSCs is hampered by the lack of an adequate method to isolate a purer population of MaSCs. It is therefore of clinical interest to discover a single surface marker than can identify and isolate a genuine population of MaSCs suitable for more complex molecular analysis. In this study, we describe Delta-like 1, a ligand of the canonical Notch signaling pathway, to be a single and efficacious surface marker of MaSCs. Our results also indicate a functional significance for Dll1 in MaSC behavior via ex vivo manipulation and transgenic mouse models. Additionally, our findings demonstrate the ability of Dll1 to serve as a cancer stem cell marker alongside its functional contribution to breast cancer tumorigenesis. Thus, the results from this study will contribute to a better understanding of Dll1 and its critical role in normal mammary gland development and progression to breast cancer.