Figure 2. A progression model of mammary epithelial cell fate specification.

Mammary epithelial differentiation occurs as cells pass through a continuous cascade of transcriptional states, with the majority of cells becoming increasingly more lineage-restricted throughout life and in response to pregnancy. Progressive lineage restriction is represented by gradual changes of the colors of cells (red, orange, yellow, green and blue). As cells differentiate, they pass through previously defined phenotypic compartments (fMaSCs, Luminal and myoepithelial (myo-epi) progenitors, mature ductal and alveolar luminal cells and mature myoepithelial cells (rectangles). Grayscale circles (ranging from white to black) on the horizontal lines represent the various epigenetic and transcriptomic states found within each phenotypic compartment with the number and different shading patterns representing the degree of heterogeneity within each major phenotypic group. Arching and angled lines connecting those circles reflect the various transcriptional and epigenetic trajectories that cells pass through before eventually terminating into mature, differentiated lineages (myoepithelial, luminal, and alveolar). Cells at various points along the differentiation cascade may serve as tumor initiators, leading to inter- and intra-tumoral heterogeneity. Figure adapted from Giraddi et al¹².