Developmental Lineage of Mammary Gland Luminal Epithelial Cells

Developmental Lineage of Mammary Gland Luminal Epithelial Cells Most postnatal mammary gland development originates from unipotent lineage-committed progenitors (luminal progenitor cells and myoepithelial progenitor cells), which are located in the basal epithelium (reviewed in Inman et al. 2015, Edwards and Brennan 2021). Based on the experiments conducted on human mammary organoids, FGF2 and FGF7 are not necessary for the differentiation of luminal epithelial cells, but they are needed for the establishment of proper architecture of mammary ducts (Pasic et al. 2011). Luminal progenitors can commit to either the ductal fate, producing luminal epithelial cells that line the mammary ducts, or to the alveolar fate, producing milk-secreting alveolar cells, with NOTCH and hormone receptor signaling playing critical roles in fate determination, so that hormone receptor positive luminal progenitor cells commit to the luminal epithelial lineage, while hormone receptor negative luminal progenitor cells commit to the alveolar lineage (reviewed in Visvader and Stingl 2014). Single cell omics studies have identified diverse subtypes of luminal progenitor cells, of which hormone receptor positive and negative have been characterized the best although not extensively (reviewed in Visvader and Stingl 2014). In human and mouse mammary glands, a putative common ancestral luminal progenitor that would give rise to hormone receptor negative and positive luminal progenitors (reviewed in Visvader and Stingl 2014) has not been identified, and it is thought that subpopulations of mammary stem cells (MaSCs) commit to either of the two luminal lineages (Hilton et al. 2012, Wang et al. 2017), but an uncommitted luminal progenitor has been described in the cow mammary gland (Perruchot et al. 2016). Both mouse and human luminal progenitor cells display plasticity and can be reprogrammed to a stem-like state by changes in the microenvironment (Shehata et al. 2012, reviewed in Visvader and Stingl 2014). Lineage tracing experiments in mouse suggest that luminal progenitors are the key drivers of mammary gland morphogenesis during puberty and alveologenesis (reviewed in Visvader and Stingl 2014). Expression of luminal, myoepithelial and stem cell markers in human luminal cells appears to be less clear-cut than what has been reported in corresponding mouse mammary cell populations (Arendt et al. 2014), but the hierarchical organization of the luminal cell compartment is similar to the one described in mouse and consists of nonclonogenic luminal cells, and relatively differentiated (EpCAM+CD49f+ALDH-) hormone receptor positive and undifferentiated (EpCAM+CD49f+ALDH+) hormone receptor negative luminal progenitors that express some genes associated with alveolar differentiation (Shehata et al. 2012). Approximately one-quarter of human breast samples may contain an additional luminal progenitor population, characterized by low expression of ERBB3 and low proliferative potential (Shehata et al. 2012), but this rare population has not been reported in other studies of the human mammary gland. Due to their plasticity, the prevalence of human luminal cell markers determined in situ may differ from the prevalence observed when luminal cells are propagated in vitro or in vivo (Shehata et al. 2012, Arendt et al. 2014). Finally, profiles of human luminal progenitor and mature cells likely differ between different breast lobule types (Arendt et al. 2014). A human breast is composed of 11-48 central ducts that radiate outward from the nipple and end in terminal ductal lobular units (TDLUs) (Arendt et al. 2014). Each lobe is composed of heterogeneous lobules at different developmental stages, where Type I lobules are the least developed and Type IV are the most developed and present only during pregnancy and lactation (Arendt et al. 2014).