Lineage-Biased Stem Cells Maintain Estrogen-Receptor-Positive and -Negative Mouse Mammary Luminal Lineages

Delineating the mammary differentiation hierarchy is important for the study of mammary gland development and tumorigenesis. Mammary luminal cells are considered a major origin of human breast cancers. However, how estrogen-receptor-positive (ER⁺) and ER^- luminal cells are developed and maintained remains poorly understood. The prevailing model suggests that a common stem/progenitor cell generates both cell types. Through genetic lineage tracing in mice, we find that SOX9-expressing cells specifically contribute to the development and maintenance of ER^- luminal cells and, to a lesser degree, basal cells. In parallel, PROM1-expressing cells give rise only to ER⁺ luminal cells. Both SOX9⁺ and PROM1⁺ cells specifically sustain their respective lineages even after pregnancy-caused tissue remodeling or serial transplantation, demonstrating characteristic properties of long-term repopulating stem cells. Thus, our data reveal that mouse mammary ER⁺ and ER^- luminal cells are two independent lineages that are maintained by distinct stem cells, providing a revised mammary epithelial cell hierarchy.