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Page 10 of 16 Anstine et al. J Cancer Metastasis Treat 2019;5:50 I http://dx.doi.org/10.20517/2394-4722.2019.24

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 [fetal mammary
stem cells (fMaSCs), Luminal and myoepithelial (myo-epi) progenitors, mature luminal (ML) ductal and alveolar 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 al. [12]

Molecular profiling studies have revealed that the gene expression patterns of cancer subtypes align with
those of normal mammary epithelial cell lineages [76,77] . This suggests that tumor subtypes may originate
from distinct mammary epithelial subpopulations. It is widely speculated that epithelial stem/progenitor
populations may serve as tumor initiating cells since their longevity and ability to self-renew affords the
accumulation of genetic mutations. This has been supported by gene expression profiling studies. For
example, the gene expression profile of claudin-low tumors most closely resembles that of MaSC/basal
epithelial cells, whereas basal-like tumors more closely resemble luminal progenitors [45,72,76,78] . Further
evidence supporting luminal progenitors as the cell of origin for the basal-like subtype has been shown in
tumors harboring BRCA-1 mutations [76,77,79] . More recently, sc-RNA-sequencing of human breast epithelial
cells demonstrated that cells expressing luminal progenitor genes correlated most highly with basal-like
[14]
breast cancers from the METABRIC dataset . Despite these findings, not all cancer subtypes have been
correlated with a cell of origin and the inability to isolate pure populations of mammary stem/progenitor
cells has impeded functional testing. Moreover, it is also feasible that cancers acquire the transcriptional
profiles of specific cell states due to the mutations that drive tumor development or progression and that the
cells of origin may not be consistent with final tumor deposition. In this case, identifying the contextual cues
that promote normal epithelial hierarchical progression would likely reveal pathways that are also activated
or suppressed in tumors that promote their phenotypes.

The new view of the mammary epithelial hierarchy suggests that the continued search for a tumor cell
of origin based on molecular profiles that have historically been used to characterize the major epithelial
populations (mature luminal, myoepithelial, luminal progenitor ext.) is unlikely to reveal discreet cells from
which different breast cancer subtypes emanate. The complexity of the normal epithelium suggests a similar
heterogeneity is present in the primary and secondary tumors that arise from it. Indeed, a study comparing
sc-RNA-seq profiles generated from triple-negative patient tumors revealed that a subset of cells within