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

Abstract

SUMMARY Delineating the mammary differentiation hierarchy is important for studying mammary gland development and tumorigenesis. Mammary luminal cells are considered a major origin of human breast cancers. However, how ER+ and ER− luminal cells are developed and maintained remains poorly understood. The prevailing model suggests that a common stem/progenitor cell generate 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 only give rise 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.

Salivary gland stem cells: A review of development, regeneration and cancer

“…Whether SOX9 continues to mark acinar progenitors and control cell fate in the SG remains to be investigated. In the pancreas SOX9+ cells become lineage restricted over time, contributing solely to the ductal lineage shortly after birth (Kopp et al , 2011), SOX9+ cells in the postnatal mammary gland give rise to estrogen receptor (ER)-negative luminal and basal cells (Malhotra et al , 2014; Wang et al , 2017) and in the hair follicle become restricted to the early bulge progeny of the outer root sheath (ORS) during the tissue growth phase known as anagen (Kadaja et al , 2014). …”

Epithelial plasticity in the mammary gland

“…Lineage-tracing of the luminal cell population has revealed that ER + progeny are restricted to the ER + lineage and, likewise, ER− progeny are restricted to the ER− lineage during pregnancy, lactation and involution 15–17 . Furthermore, Wap-Cre, which is active only during pregnancy in the ER − alveolar cells, marked only ER − labeled cells after two pregnancies 18 .…”

Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention

“…These studies, together with select lineage tracing reports, document the presence of a bi‐potent basal population (Rios et al , ; Wang et al , ). However, other lineage tracing studies challenge this classical view, proposing instead that the combined action of unipotent basal and luminal progenitors maintains the mammary gland (Van Keymeulen et al , ; Giraddi et al , ; Wuidart et al , ; Wang et al , ). Despite ongoing discussion in this area, a considerable body of work supports specific mammary populations as the candidate cells‐of‐origin for breast cancer subtypes.…”