Role of epithelial stem/progenitor cells in mammary cancer

Abstract

Both mouse and human mammary glands contain stem/progenitor functional hierarchies that are maintained through the entire life span of the animal. Cells with such functional capacities are potential candidates for tumorigenesis as they are long lived, multipotent, and self-renewing. Using the mouse as a model, this review will discuss what is known about the mammary stem/progenitor hierarchy, the evidence that particular progenitor functions are susceptible to tumorigenic stimuli, how these findings in mice are relevant to the disease in humans, and the role of the local microenvironment in controlling tumorigenesis.

Figure 1

Example of an undifferentiated large light cell (ULLC). The ULLC maintains contact with the lumen and the basement membrane. Note the complex cytoplasm of the surrounding differentiated cells as compared to the ULLC. Scale bar: 5 μm.

Figure 2

Model of stem/progenitor cellular hierarchy in the mouse mammary gland. The pluripotenet stem cell gives rise to duct-limited and lobule-limited (PI-MEC) progenitors. Both progenitor populations are multipotent. The lobule progenitor gives rise to ER^+/− and PR^+/− luminal epithelial cells and myoepithelial cells. Duct-limited progenitors also give rise to ER^+/− and PR^+/− luminal epithelial cells as well as the cap cells during ductal elongation. The cap cells ultimately differentiate into the myoepithelial cells of the ducts. Arrows indicate potential and identified targets of the oncogenic stimuli listed.

Figure 3

Cells derived from MMTV-Neu/WC/R26 tumors contribute to a functional mammary gland when mixed with normal mammary epithelium. (A) When inoculated on their own, MMTV-Neu/WC/R26 tumor cells give rise to tumors in cleared mammary fat pads. (B) When mixed with normal mammary epithelium in a 1:50 ratio and inoculated into an epithelial divested fat pad, the β-Gal-marked tumor cells contribute to the resulting normal mammary outgrowth and did not produce tumors. (C) Cross section of a chimeric gland demonstrating presence of β-Gal⁺ cells. (D) β-Gal and casein coexpression (white) in mammary epithelium in a lactating chimeric gland demonstrates tumor-derived cells capable of differentiating to producing milk proteins.