Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis

Abstract

The epithelium of the mammary gland exists in a highly dynamic state, undergoing dramatic morphogenetic changes during puberty, pregnancy, lactation, and regression. The recent identification of stem and progenitor populations in mouse and human mammary tissue has provided evidence that the mammary epithelium is organized in a hierarchical manner. Characterization of these normal epithelial subtypes is an important step toward understanding which cells are predisposed to oncogenesis. This review summarizes progress in the field toward defining constituent cells and key molecular regulators of the mammary epithelial hierarchy. Potential relationships between normal epithelial populations and breast tumor subtypes are discussed, with implications for understanding the cellular etiology underpinning breast tumor heterogeneity.

Figure 1.

Schematic representations of a duct (A) and a TEB (B). A suprabasal cell sits on the myoepithelial layer but does not reach the lumen.

Figure 2.

Schematic representations of the human and mouse mammary glands.

Figure 3.

Model of the differentiation hierarchy within mammary epithelium. Primary cell surface markers used in the isolation of mouse and human epithelial cell subsets are shown in blue and red, respectively. (ER) ERα. The common progenitor is also referred to as a bipotent progenitor cell. There may be a hierarchy of stem and bipotent progenitor cells. During pregnancy, the alveolar progenitor may exhibit bipotential capacity.

Figure 4.

Transcriptional regulators and molecular pathways that influence discrete cell types and stages along the mammary epithelial hierarchy. These have been demonstrated to affect MaSC self-renewal, lineage commitment, or luminal differentiation. Plus (+) and minus (−) signs refer to positive or negative effects on self-renewal.

Figure 5.

Schematic model of the human breast epithelial hierarchy and potential relationships with breast tumor subtypes. The six different tumor types are shown together with their closest normal epithelial counterpart based on gene expression analyses. The luminal progenitor subtype may be a more appropriate name for basal tumors. The HER2 subtype could originate through amplification of the HER2 locus in a target cell restricted to the luminal cell lineage.