Mammary gland hormone receptor negative luminal progenitor cells, which do not express estrogen (ESR) or progesterone receptors (PGR), commit to an alveolar fate in both humans and mice, producing milk-secreting alveolar cells, also known as secretory lactocytes (Shehata et al. 2012, Martin Carli et al. 2020, reviewed in Visvader and Stingl 2014). Hormone receptor positivity may be important for responding to hormonal/secretory signals elicited during pregnancy and lactation (Hilton et al. 2012). Luminal progenitors produce alveolar progenitors, which are hormone receptor negative (Martin Carli et al. 2020, predicted in review by Visvader and Stingl 2014). The commitment of luminal progenitors to alveolar fate is induced during pregnancy (reviewed in Visvader and Stingl 2014). 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). Expression of PPM1D (Wip1 phosphatase) in mouse hormone receptor positive luminal cells is needed for RANKL transcription, and the requirement for PPM1D can be overridden by ectopic overexpression of ERBB2 in mouse alveolar progenitors, probably through ERBB2-stimulated activation of STAT5 signaling (Tarulli et al. 2013). 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). Based on the study by Martin Carli et al. 2020, however, 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, but it is increased in alveolar progenitors which are at a more advanced stage of differentiation compared to hormone receptor negative luminal progenitors (Martin Carli et al. 2020). The transcription factor EHF is highly expressed in the lactating mammary gland, including in alveolar progenitors isolated from human milk (Martin Carli et al. 2020). The mRNA expression profiles of human milk-derived alveolar progenitors and hormone receptor negative luminal progenitors, the latter considered to be at earlier stages of alveolar differentiation, are quite similar overall (Martin Carli et al. 2020). Compared to hormone receptor negative luminal progenitors, alveolar progenitors show increasing expression levels of milk secretion-related proteins and do not express some of the markers of hormone receptor negative luminal progenitors, such as ALDH1A3, CLD4, and ITGA6 (Martin Carli et al. 2020). In mice, loss of Ehf gene impairs mammary lobuloalveolar differentiation at late pregnancy, resulting in significantly reduced levels of milk genes and milk lipids, fewer differentiated alveolar cells, and an accumulation of alveolar progenitor cells (Nightingale et al. 2024). Low EHF expression is associated with higher tumor grades and poorer outcomes in luminal A and basal human breast cancers, supporting the role of EHF as a regulator of mammary alveolar differentiation and a putative suppressor of mammary tumorigenesis (Nightingale et al. 2024). After cessation of lactation, alveolar cells in the mammary gland die during the involution process, however, mouse lineage tracing studies suggest that some alveolar progenitors/precursors survive the involution and function as self-renewing alveolar precursors in subsequent pregnancies (Chang et al. 2014, reviewed in Visvader and Stingl 2014).

Markers of mammary alveolar progenitor cells are shown 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):