Developmental Lineages of the Mammary Gland

Mammary gland development begins in the embryo with the formation of the lens‑like mammary placodes around embryonic day 10 (E10) in mice (five pairs). The mammary placode appears as a thickening of the ectoderm and consists largely of epithelial cells (reviewed in Watson and Khaled 2020). In humans, the first signs of breast development are seen around gestational week GW5, when a 2–4 cell layer mammary line (also known as milk streak or mammary band) appears as a thickening in the ectoderm that extends from the axilla to the groin (reviewed in Gusterson and Stein 2012). The milk line is not visible during mouse mammary gland development. During GW6 and GW7, a thickening in the thoracic region, called the mammary crest, forms a four to six cell‑wide ridge, while the rest of the milk line involutes (reviewed in Gusterson and Stein 2012). Subsequently, mammary crest forms into a nodule that begins sinking into differentiating mesenchyme, forming a flask‑shaped structure, which is accompanied by nipple formation, and followed by the downgrowth of a number of tubes of epithelium into the stroma to form the early major ducts, all together constituting a structure known as the primary bud (reviewed in Gusterson and Stein 2012). The major ducts continue to grow, along with side branches, from the primary bud, developing a lumen and becoming lined by two layers of cuboidal cells (reviewed in Gusterson and Stein 2012). A very large variation in the degree of fetal mammary gland development is observed in neonates, which is probably attributable to differences in maternal hormone level and nutrition (reviewed in Gusterson and Stein 2012).

In mice, critical molecular signaling pathways active during this stage that ensure the correct placement and early formation of the gland have been characterized in a lot more detail than in humans (reviewed in Gusterson and Stein 2012). Many of the signaling pathways identified in mouse fetal mammary gland development are regulated by paracrine factors secreted by mesenchymal cells that surround the mammary placode. Wnt/β‑catenin signaling is crucial for the initiation of mammary placode formation (reviewed in Lindvall et al. 2007). Wnt ligands (such as Wnt4 and Wnt10b) bind to their receptors (Frizzled and co‑receptors like LRP5/6), leading to the stabilization and nuclear translocation of β‑catenin (Ctnnb1) (reviewed in Lindvall et al. 2007). Once in the nucleus, β‑catenin interacts with LEF1:TCF transcription factor complexes, driving the expression of genes required for the epithelial thickening and subsequent formation of the mammary placode (reviewed in Lindvall et al. 2007).

This module describes four cell developmental lineages of the mammary gland: mammary stem cells, mammary luminal epithelial cells, mammary alveolar cells, and mammary myoepithelial cells.

The developmental lineage of mammary stem cells (MaSCs) is derived from embryonic non-neural surface ectoderm cells. In the mouse, MaSCs are defined as those cells that are able to generate a functional mammary gland when transplanted in vivo, but there is evidence that mouse MaSCs isolated at different stages of mammary gland morphogenesis are not completely identical. Most data available on human MaSCs is derived from adult stem-like cells in human mammary glands that are able to differentiate in vitro into both myoepithelial and ductal (luminal) epithelial cells and thus are also known as mammary bipotent progenitors (MBiPs), and it is uncertain how much these adult human MaSCs/MBiPs differ from human embryonic and fetal MaSCs (reviewed in Phillips and Kuperwasser 2014).

The developmental lineage of mammary gland luminal epithelial cells shows two branches of luminal progenitors, the ones committed to the ductal fate and the ones predisposed to the alveolar fate, and development of luminal ductal epithelial cells that line mammary ducts from the former ones (reviewed in Visvader and Stingl 2014).

The developmental lineage of mammary gland alveolar cells show the differentiation of milk-secreting lactocytes that line the alveoli of the mammary gland, which is initiated during pregnancy (reviewed in Visvader and Stingl 2014).

The developmental lineage of mammary gland myoepithelial cells shows the development of spindle shaped myoepithelial cells that form the sheath around the mammary ducts and alveoli, contracting in response to oxytocin to enable milk secretion (reviewed in Stingl et al. 2005, Watson and Khaled 2020).