Stem cells in the human breast

Abstract

The origins of the epithelial cells participating in the development, tissue homeostasis, and cancer of the human breast are poorly understood. However, emerging evidence suggests a role for adult tissue-specific stem cells in these processes. In a hierarchical manner, these generate the two main mammary cell lineages, producing an increasing number of cells with distinct properties. Understanding the biological characteristics of human breast stem cells and their progeny is crucial in attempts to compare the features of normal stem cells and cancer precursor cells and distinguish these from nonprecursor cells and cells from the bulk of a tumor. A historical overview of research on human breast stem cells in primary tissue and in culture reveals the progress that has been made in this area, whereas a focus on the cell-of-origin and reprogramming that occurs during neoplastic conversion provides insight into the enigmatic way in which human breast cancers are skewed toward the luminal epithelial lineage.

Figure 1.

Fetal human breast. Schematic representation of a fetal human breast at the primary bud stage (upper row), the secondary bud stage (middle row), and the neonatal stage (lower row). Nuclei, keratin K14 and keratin K19 are represented by blue, green, and red, respectively. At the primary bud stage, the human breast primordium consists of an inner layer of central primary bud cells and an outer layer of basal primary bud cells surrounded by mesenchyme. Significantly, the basal primary bud cells differ from the basal epidermal cells by the lack of keratin K14. At the secondary bud stage mammary projections are characterized by the dual expression of keratins K14 and K19. At the neonatal stage the luminal and basal epithelial lineages are clearly separated. Double-positive cells for keratin K14 and K19 are scattered in terminal lobular units and end buds.

Figure 2.

Postnatal human breast. Multicolor imaging (left column) and schematic representation (right column) of cryostat sections of the human breast at the infant (upper row), adult (middle row), and lactating (lower row) stage stained against nuclei (blue), keratin K14 (green), and keratin K19 (red). Whereas the infant breast consists of up to three cell types in terms of keratin K14 and K19 expression (−/+; +/−, and rare +/+) the adult breast shows a fourth cell type being double-negative (−/−). These cells are luminal and may expand clonally and differentiate during lactation side by side with +/− lobules (Scale bar = 50 µm).

Figure 3.

Schematic model of the human breast lineage hierarchy at different developmental stages. The most primitive fetal cells are double-negative for keratin K14 and K19 represented with a blue cytoplasm. Stem cells in the infant and adult human breast are thought to be lineage primed along the basal lineage represented by a light green cytoplasm. Multipotent progenitor cells are double-positive for keratin K14 and K19 represented by a yellow cytoplasm. Differentiated breast basal/myoepithelial and epithelial cells are either positive for keratin K14 (green), keratin K19 (red), double positive (yellow), or double negative (blue). Additional markers are listed for the different classes of cells in the adult breast.

Figure 4.

Keratin K19/K14 breast cancer subtypes. Multicolor imaging of cryostat sections of human breast carcinomas representing different subtypes as defined by combinations of staining with keratin K19 and K14. In a sample of 50 randomly selected primary breast carcinomas, 6 were double-positive for keratin K19 and K14 (A), 43 were positive for keratin K19 only (B), 1 was double-negative (C), and none of them were positive for keratin K14 alone (D; staining of a malignant myoepithelioma from a different sample) (Scale bar = 50 µm).