A new view of the mammary epithelial hierarchy and its implications for breast cancer initiation and metastasis.

The existence of mammary epithelial stem cell (MaSC) populations capable of mediating mammary gland development and homeostasis has been established for over a decade. A combination of lineage tracing and mammary gland transplantation studies has affirmed that MaSCs and their downstream progenitors are organized in a hierarchal manner; however, these techniques have failed to illuminate the complete spectrum of epithelial intermediate populations or their spatial and temporal relationships. The advent of single cell sequencing technology has allowed for characterization of highly heterogeneous tissues at high resolution. In the last two years, the remarkable advances in single cell RNA sequencing (scRNA-seq) technologies have been leveraged to address the heterogeneity of the mammary epithelium. These studies have afforded fresh insights into the transcriptional differentiation hierarchy and its chronology. Importantly, these data have led to a major conceptual shift in which the rigid boundaries separating stem, progenitor, and differentiated epithelial populations have been deconstructed, resulting in a new more fluid and flexible model of epithelial differentiation. The emerging view of the mammary epithelial hierarchy has important implications for mammary development, carcinogenesis, and metastasis, providing novel insights into the underlying cellular states that may promote malignant phenotypes.