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Page 2 of 9 Robinson et al. J Cancer Metastasis Treat 2019;5:39 I http://dx.doi.org/10.20517/2394-4722.2019.15

INTRODUCTION
Breast cancer is the most common malignancy and most frequent cause of cancer-related death in women
globally . The vast majority of breast cancer-related morbidity and mortality can be ascribed to metastasis,
[1]
[2,3]
which occurs in ~30 percent of cases and underlies ~90 percent of breast cancer deaths . Metastasis is
a multistage cascade that commences when cancer cells migrate from their primary tumor of origin and
undergo hematogenous dissemination that terminates in the seeding and colonization of distant organs .
[4]
This so-called “invasion-metastasis cascade” serves as an evolutionary bottleneck that requires disseminated
tumor cells (DTCs) to: (1) activate migratory and invasive programs; (2) survive within the vasculature in an
anchorage- independent manner; (3) interact with other circulating cells to facilitate survival and extravasation;
and (4) coordinate tissue-specific signaling inputs to persist in unfamiliar microenvironments . Thus,
[5-7]
metastasis can be viewed as a process of clonal selection whereby a heterogeneous primary tumor gives
rise to subpopulations that are fit to traverse the invasion-metastasis cascade. Following tissue colonization,
these disseminated subclones retain growth-permissive features of the original primary tumor and undergo
further evolution and clonal expansion within metastatic microenvironments .
[8,9]

Metastatic evolution occurs via a number of distinct yet spatiotemporally overlapping mechanisms,
including linear and parallel progression of monophyletic or polyphyletic founder clones . Cancer stem
[10]
cells (CSCs) are fundamental components of tumors that enable the maintenance of emergent clonal
populations yielded by evolutionary forces [11-13] . CSCs are operationally defined by their self-renewal and
tumor-initiating capacities; that is, a single CSC can recapitulate a tumor in its entirety, including a stable
CSC pool . Historically, stochastic clonal evolution was believed to be mutually exclusive with a tumor
[14]
developmental hierarchy built upon a stem cell population [15,16] . More recent evidence suggests that there is a
relationship between tumor evolution and CSCs that manifests through at least two mechanisms. First, the
CSC population itself becomes highly heterogeneous during tumor development, indicating that CSCs are
directly subjected to selective pressures [17,18] . Second, non-stem cancer cells that define unique genetic and
epigenetic lineages can be reprogrammed into CSCs [19,20] . Thus, the plasticity that exists within and between
stem and non-stem cancer cells provides a bidirectional route to engender clones that harbor distinctive
properties, including the ability to metastasize. Of note, the functional significance of CSC evolution in the
development and progression of multiple malignancies has been extensively documented [21-23] .

Numerous pathways that exert control over the metastatic propensity of cancer cells do so by regulating
the production or function of CSCs. For instance, Wnt/β-catenin signaling in both the primary tumor
and metastatic microenvironments enhances breast CSC self-renewal and metastatic colonization [24,25] .
Likewise, inhibiting Wnt signaling abrogates metastatic outgrowth by depleting the CSC population [26,27] .
Similarly, vascular endothelial growth factor (VEGF) activates stem programs in breast cancer cells via
VEGF receptor (VEGFR)-and neuropilin (NRP)-dependent cascades [28,29] . VEGF can additionally push
breast CSCs to undergo endothelial-like differentiation, thereby promoting tumor vascularization and
cancer cell dissemination . The NF-κB transcription factor pathway also acts as a critical regulator of breast
[30]
CSC function . In particular, microenvironmental stimuli from resident stromal cells, extracellular matrix
[31]
components, and the local immune milieu activate NF-κB signaling to sustain CSC development [25,32,33] . As
[34]
a result, NF-κB inhibitors demonstrate potent activity against breast CSCs . Related to these events, CSC
expansion is associated with the epithelial-mesenchymal transition (EMT), a process whereby epithelial cells
lose their intrinsic polarity and markers of differentiation and adopt features of mesenchymal cells, including
enhanced migration and invasiveness [35,36] . Key transcription factors that orchestrate EMT in breast cancer,
such as Snail, Slug, and Twist1, simultaneously play a role in the acquisition of stem-like traits . Importantly,
[37]
both Wnt/β-catenin and NF-κB signaling exert direct transcriptional control over these EMT-associated
factors [36,38] . Furthermore, EMT induces upregulation of VEGF, which bolsters the activities of β-catenin
and NF-κB and promotes angiogenesis to support CSC self-renewal and permit dissemination [39-41] . In short,
breast CSC survival and maturation are determined by a confluence of cell-intrinsic and microenvironment-
derived signals that are transduced through parallel EMT-dependent and -independent circuits.