The mammary gland is a highly dynamic organ that undergoes profound changes within its epithelium during puberty and the reproductive cycle. These changes are fueled by dedicated stem and progenitor cells. Both short-and long-lived lineage-restricted progenitors have been identified in adult tissue as well as a small pool of multipotent mammary stem cells (MaSCs), reflecting intrinsic complexity within the epithelial hierarchy. While unipotent progenitor cells predominantly execute day-to-day homeostasis and postnatal morphogenesis during puberty and pregnancy, multipotent MaSCs have been implicated in coordinating alveologenesis and long-term ductal maintenance. Nonetheless, the multipotency of stem cells in the adult remains controversial. The advent of large-scale single-cell molecular profiling has revealed striking changes in the gene expression landscape through ontogeny and the presence of transient intermediate populations. An increasing number of lineage cell-fate determination factors and potential niche regulators have now been mapped along the hierarchy, with many implicated in breast carcinogenesis. The emerging diversity among stem and progenitor populations of the mammary epithelium is likely to underpin the heterogeneity that characterizes breast cancer.

This review summarizes recent advances in understanding normal cell types in the mammary gland (breast), their potential lineage relationships, and the roles of molecular regulators in fate specification and differentiation. The mammary epithelial hierarchy provides an important framework for deciphering the cell types necessary for normal physiological function as well as understanding perturbations that lead to breast cancer. The prospective isolation of stem and progenitor cells, informed by both in vivo transplantation and lineage tracing experiments, has helped to shed light on the cell of origin for distinct subtypes of breast cancer. For example, a hyperproliferative RANK+ luminal progenitor cell appears to be the culprit cell that gives rise to triple-negative breast cancer in women harboring a germline mutation in the BRCA1 gene. This has revealed a targetable cell for chemoprevention. Female steroid hormones (estrogen and progesterone) and key regulators (eg, Notch pathway, GATA-3) are instrumental for normal development, and their deregulated expression is implicated in breast cancer. The microenvironment is also emerging as an important regulator of mammary gland development and neoplasia. Finally, the reactivation of embryonic developmental programs and emergence of cellular‟ plasticityˮ appear to play important roles in breast cancer.