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Review
. 2022 Mar 31;23(7):3883.
doi: 10.3390/ijms23073883.

The Mammary Gland: Basic Structure and Molecular Signaling during Development

Swarajit Kumar Biswas  1 , Saswati Banerjee  2 , Ginger Wendolyn Baker  3 , Chieh-Yin Kuo  4 , Indrajit Chowdhury  3
Affiliations
Review

The Mammary Gland: Basic Structure and Molecular Signaling during Development

Swarajit Kumar Biswas et al. Int J Mol Sci. .

Abstract

The mammary gland is a compound, branched tubuloalveolar structure and a major characteristic of mammals. The mammary gland has evolved from epidermal apocrine glands, the skin glands as an accessory reproductive organ to support postnatal survival of offspring by producing milk as a source of nutrition. The mammary gland development begins during embryogenesis as a rudimentary structure that grows into an elementary branched ductal tree and is embedded in one end of a larger mammary fat pad at birth. At the onset of ovarian function at puberty, the rudimentary ductal system undergoes dramatic morphogenetic change with ductal elongation and branching. During pregnancy, the alveolar differentiation and tertiary branching are completed, and during lactation, the mature milk-producing glands eventually develop. The early stages of mammary development are hormonal independent, whereas during puberty and pregnancy, mammary gland development is hormonal dependent. We highlight the current understanding of molecular regulators involved during different stages of mammary gland development.

Keywords: development; mammary gland; signaling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The mammary gland. (A) Schematic representation of adult human mammary gland anatomy. The mammary gland (exocrine sudoriferous or sweat gland) is located on the ventral chest wall superficial to the pectoralis muscles. The basic components of a mature mammary gland are the alveoli (hollow cavities, a few millimeters large) lined with milk-secreting cuboidal cells and surrounded by myoepithelial cells. These alveoli join together to form lobules surrounded by adipose and connective tissues. Each lobule has a lactiferous duct that drains into openings in the nipple through lactiferous sinus. The nipple is surrounded by the pigmented areola with sweat and sebaceous glands. (B) Schematic representation of a terminal end bud (TEB). Mature ducts are comprised of luminal epithelial cells surrounded by contractile myoepithelial cells, fibrous connective tissue, and variable amounts of adipose tissue. At puberty, these swell into TEBs. TEBs consist of multiple layers of body cells and a single layer of cap cells at the leading edge. The subtending ducts are surrounded by a variety of stromal cells or connective tissues with extracellular matrix (ECM) protein supports the mammary glands. The major components of stromal connective tissues are adipocytes, fibroblasts, vascular endothelial cells, a variety of innate immune cells (both macrophages and mast cells), and nerves. The fatty stroma is the supportive network for the epithelium bi-layered structure and provides nutrients, blood supply, and immune defenses besides the physical structure to the gland. TEBs are regulated hormonally by estrogens (E2) and progesterone (P4) from the corpus luteum and placenta, prolactin (PRL) from the anterior pituitary, and oxytocin from the posterior pituitary gland. TEBs respond to autonomic nervous system impulses.
Figure 2
Figure 2
A schematic representation of the origin of epithelial–mesenchymal cells and prenatal mammary development from embryonic to adult stage. The primary mesenchyme forms with gastrulation in mammals provide the first distinction between epithelial and mesenchymal phenotypes. Cells exhibiting a mesenchymal phenotype provide a supportive structure to the epithelial cells by producing the extracellular matrix (ECM). The transition of epithelial and mesenchymal cells forms the primary mesenchyme and three primitive germ layers, namely, ectoderm, mesoderm, and endoderm. The mammary epithelium comprises several cell lineages, including luminal, alveolar, and myoepithelial cells. The mammary epithelium is maintained by the presence of multipotent mammary stem cells (MaSCs). MaSCs provide unipotent stem cells with the extensive renewing capacity to luminal and myoepithelial lineages during neonatal, pubertal, and pregnancy stages. All the adult MaSC population is maintained by signals from their specialized local microenvironment or niche. During puberty, the expansion and maintenance of each lineage are ensured by the presence of two types of lineage-restricted stem cells that can differentiate into either myoepithelial or luminal lineages. Mammary stem cells are self-renewed in their niche. Asymmetrically dividing stem cells produce transit-amplifying daughter cells that commit to basal or luminal progenitor lineages.
Figure 3
Figure 3
A schematic representation of different stages of mammary gland development connecting with embryonic mammary primordial, followed by the different postnatal stages along with key hormone dependent phases vs. independent phases, key transcription factors, and signaling molecules. The single circle represents terminal end buds (TEBs) during puberty, whereas multiple circles represent lubloalveolar units.
Figure 4
Figure 4
A schematic representation of major signal transduction pathways and their interaction during mammary gland development. Hepatocyte growth factor (HGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) signal through receptor tyrosine kinases (RTK) activates the central Ras-Raf-MAPK pathway or the PI3K pathway and the Src-STAT pathway. Transforming growth factor (TGF)-β signals through the receptor serine/threonine kinases (RS/TK) activates the central R-Smad/Co-Smad pathway or the PI3K and MAPK pathways or Wnt pathway. Jagged and Delta-like ligands signal through Notch receptors regulates the transcription factor CSL. Wnt ligands signal through Frizzled receptors regulates β-catenin and the transcription factors LEF-1/TCF. All these pathways together regulate gene expressions and that determines EMT. The white circles with dotted lines represent the transcription factors.
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