The mammary cellular hierarchy and breast cancer

Abstract

Advances in the study of hematopoietic cell maturation have paved the way to a deeper understanding the stem and progenitor cellular hierarchy in the mammary gland. The mammary epithelium, unlike the hematopoietic cellular hierarchy, sits in a complex niche where communication between epithelial cells and signals from the systemic hormonal milieu, as well as from extra-cellular matrix, influence cell fate decisions and contribute to tissue homeostasis. We review the discovery, definition and regulation of the mammary cellular hierarchy and we describe the development of the concepts that have guided our investigations. We outline recent advances in in vivo lineage tracing that is now challenging many of our assumptions regarding the behavior of mammary stem cells, and we show how understanding these cellular lineages has altered our view of breast cancer.

Fig. 1

The stem cell niche during mammary development and carcinogenesis. a Traditional view of the mammary hierarchy: a mammary stem cell resides at the top of the hierarchy, present in the embryonic mammary gland and possibly in the adult. It gives rise to committed bipotent progenitor cells, which under the influence of extracellular and intracellular cues give rise to progenitors and mature cells in their respective lineages. b The mammary hierarchy exists within a cellular niche that has different activities, and locations, with each developmental stage. c The activity of the niche is disrupted during carcinogenesis, the exact nature of which may produce the heterogeneous cancer subtypes observed

Fig. 2

Mammary gland development, embryonic to pregnancy and beyond. a The mammary gland emerges from mammary placodes that form along the milk line at embryonic day 10–11. At birth, the mammary epithelium emerges from the placode and grows isometrically until puberty when rapid expansion of the epithelium extends the ducts throughout the fat pad. Ductal side branches sprout from the lateral surfaces of the ducts in multiple rounds of proliferation throughout each estrous cycle and results with the complete filling of the mammary fat pad. This process is collectively termed ductal morphogenesis. Pregnancy induces alveolar morphogenesis where proliferation establishes the alveolar epithelium, which then differentiates into milk-secreting alveoli at mid-pregnancy (lactogenesis I/secretory initiation). The final phase of differentiation results in milk and lipid movement into the alveolar lumens ready for lactation (Lactogenesis II/secretory activation). Milk ejection maintains lactation, and after weaning the mammary gland undergoes rapid programmed cell death (involution), returning the gland to a near-virgin state. b Mammary whole mounts (Carmine alum stain top row) and mammary cellular architecture (hematoxylin and eosin histology bottom row) in virgin, 6 days post coitus (dpc), 12 dpc, 18 dpc and 1-day postpartum (1dpp) murine mammary glands. Ductal epithelial cells (arrow), myoepithelial cells (arrowhead) and adipocytes (A) are indicated. Alveoli form a sphere-like single layer of epithelial cells enveloping a circular lumen (X) and contain cytoplasmic lipid droplets from 18 days post coitus, after secretory initiation (asterisk). At parturition, tight junctions between alveolar cells close and milk proteins and lipid are secreted into the alveolar lumen (X). An expansion of the vasculature (open arrows) and reduction in area is also apparent in the stroma