SCA-1 labels a subset of estrogen-responsive bipotential repopulating cells within the CD24⁺ CD49f^hi mammary stem cell-enriched compartment

Estrogen stimulates breast development during puberty and mammary tumors in adulthood through estrogen receptor-α (ERα). These effects are proposed to occur via ERα⁺ luminal cells and not the mammary stem cells (MaSCs) that are ERα^neg. Since ERα⁺ luminal cells express stem cell antigen-1 (SCA-1), we sought to determine if SCA-1 could define an ERα⁺ subset of EpCAM⁺/CD24⁺/CD49f^hi MaSCs. We show that the MaSC population has a distinct SCA-1⁺ population that is abundant in pre-pubertal mammary glands. The SCA-1⁺ MaSCs have less stem cell markers and less in vivo repopulating activity than their SCA-1^neg counterparts. However, they express ERα and specifically enter the cell cycle at puberty. Using estrogen-deficient aromatase knockouts (ArKO), we showed that the SCA-1⁺ MaSC could be directly modulated by estrogen supplementation. Thus, SCA-1 enriches for an ERα⁺, estrogen-sensitive subpopulation within the CD24⁺/CD49f^hi MaSC population that may be responsible for the hormonal sensitivity of the developing mammary gland. Mouse mammary stem cells are thought to be estrogen-receptor negative and receive hormonal influence via estrogen-receptor-positive luminal neighbors. In this article, Britt and colleagues describe a population within the mammary stem cell-enriched compartment that is estrogen-receptor positive and directly responsive to estrogens. This has implications for understanding how aberrant hormone exposure affects breast cancer risk.