Colony-forming assays that use mammary stem-like cells (M...

Colony-forming assays that use mammary stem-like cells (MaSCs)/bipotent progenitor cells isolated from normal adult human mammary glands, show that MaSCs form mixed colonies which include luminal progenitor cells (Stingl et al. 2005, Raouf et al. 2008, Hilton et al. 2012). For a detailed description of MaSCs/bipotent mammary gland progenitors, please refer to the module Developmental Lineage of Mammary Stem Cells. The majority of MaSCs in normal adult human mammary glands and luminal progenitor cells derived from them do not express estrogen (ESR) or progesterone receptors (PGR) (Hilton et al. 2012). Lineage tracing studies in mouse show that ESR-negative luminal cells as well as alveolar cells are derived from SOX9-positive luminal progenitors that are also ESR-negative (Wang et al. 2017). These ESR-negative luminal progenitors might be derived from the SOX9-positive subpopulation of MaSCs that also gives rise to myoepithelial progenitors (Wang et al. 2017). The existence of similar progenitors in the human breast, that can give rise to one branch of luminal cells and to myoepithelial cells, has also been reported (Stingl et al. 1998). These cells express a lower level of MUC1 compared to more luminally committed progenitors, express EPCAM, and may show some expression of the myoepithelial progenitor marker MME (CD10) (Stingl et al. 1998). While Stingl et al. 1998 suggested these progenitors to be putative ductal progenitors (i.e. hormone receptor-positive luminal progenitors), their phenotype is better aligned with hormone receptor-negative luminal progenitors described in subsequent studies. Lineage tracing studies in mouse have shown that luminal progenitors that give rise to alveolar progenitors and subsequently milk-secreting lactocytes are negative for PGR but express the transcription factor ELF5, necessary for alveolar differentiation and milk secretion (Lee et al. 2013). PGR stimulates secretion of the cytokine TNFSF11 (also known as RANKL) from PGR-positive mature luminal epithelial cells that serve as luminal hormone-sensing cells (LHS), and RANKL stimulates expression of ELF5 in PGR-negative luminal progenitors (Lee et al. 2013). A subsequent mouse study showed that RANKL inhibits ELF5 expression at midpregnancy (Cordero et al. 2016). This suggests that RANKL may have a dual role during alveolar differentiation, being essential during early alveolar development, but serving to limit prolactin-stimulated alveolar development later in pregnancy (Cordero et al. 2016). RANKL is expressed in hormone receptor-positive mature luminal epithelial cells from human breasts (Lim et al. 2010). Normal adult human breasts also contain a subpopulation of PGR-negative and ELF5-positive luminal progenitors, also called luminal adaptive secretory progenitors (LASPs) (Lim et al. 2010, Nguyen et al. 2018, Reed et al. 2024), but based on the study by Martin Carli et al. 2020, which analyzed single cells isolated from human milk, the expression of ELF5 is not differentially increased in hormone receptor-negative luminal progenitors that give rise to the alveolar lineage.

In mouse, the existence of long-lived unipotent luminal stem cells that survive consecutive involutions and retain their identity throughout adult life was reported, and these luminal stem cells were shown to be Prdm1 (Blimp1)-positive, but to give rise to the Prdm1-negative progeny that is Elf5+Esr1-Pgr- (Elias et al. 2017).

Markers of hormone receptor negative mammary luminal progenitors are listed in the table below (in the table, "No" means that the marker is not listed for the specified cell type while "N/A" means that the specified cell type is not annoted in the cited external marker database).

EGFR protein is detectable at the surface of ~ 50% of luminal progenitor cells derived from MaSC-like cell of the normal adult human breast (Stingl et al. 2001). EGFR is detectable in luminal progenitor cells derived from MCF10A human mammary epithelial cell line but expressed at a lower level than in MaSCs and myoepithelial progenitor cells (Phillips et al. 2014). EGFR is therefore not annotated as a marker of human mammary luminal progenitor cells.

EGFR ligands EGF and AREG stimulate in vitro differentiation of MaSCs into luminal lineage, while EGFR ligand TGFA inhibits it (Pasic et al. 2011, Mukhopadhyay et al. 2013).

Expression of NOTCH4 mRNA, which is associated with MaSC phenotype (Bachelard-Cascales et al. 2010, Lim et al. 2010, Coradini et al. 2014), is downregulated in mammary luminal progenitor cells (Coradini et al. 2014).

KRT18 mRNA expression in mammary luminal progenitor cells of normal adult human breast is low compared to mature luminal epithelial cells (Prat et al. 2013). KRT8 is expressed at a low level in luminal progenitor cells and thus not annotated as a marker (Nguyen et al. 2018).