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despite the relative abundance of tumor cells traversing the vascular systems of some patients, the process of
metastasis remains a supreme inefficient event. Indeed, animal modeling studies estimate that only ~0.01%
[15]
of circulating tumor cells are capable of initiating some form of metastatic outgrowth , and as such, it
is the late stages of metastatic progression that ultimately dictate the competency of disseminated cells in
[12]
establishing overt metastases within the metastatic niche .

Dormancy: a metastatic bottleneck
The acquisition of metastatic phenotypes was originally believed to be an evolutionary consequence of
advanced, late-stage disease. However, recent findings indicate that carcinoma cells comprising primary
breast tumors do in fact enter the circulation months-to-years prior to the point at which the primary tumor
[16]
becomes symptomatic and diagnosable . As such, a large proportion of breast cancer patients already
harbor disseminated tumor cells (DTCs) at their time of diagnosis [11,17,18] . Indeed, DTCs are readily detected
in the bone marrow of 30%-40% of patients diagnosed with early-stage breast cancer, an event that portends
a significantly worse prognosis as compared to patients whose bone marrow is free from DTCs at the time
[19]
of diagnosis . Interestingly, a large fraction of these DTCs initially remain clinically asymptomatic due in
part to their acquisition of dormancy-associated phenotypes upon arrival to the micrometastatic niche [12] .

Although diverse genetic and epigenetic analyses have begun to reveal the molecular landscape that
characterizes metastatic breast cancers, only recently have these investigations been directed at and tailored
for DTCs and their reactivation of proliferative programs during metastatic relapse. As such, a unified
definition of dormancy remains elusive. At a cellular level, current models suggest that metastatic cells often
undergo proliferative arrest upon arriving to a micrometastatic niche, a phenomenon believed to reflect
[20]
the initial maladaptation of DTCs to foreign stromal environments . Indeed, the stromal characteristics
that impact DTC dormancy are multifactorial and encompass a diverse array of immunomodulatory
and vascular endothelial cell signals (e.g., cytokine milieu, rigidity of the microenvironment, presence
of active immunosurveillance [17,21,22] ) that converge on niche-localized DTCs. In doing so, these unique
microenvironment signals may prove to be inhospitable to DTCs, thereby provoking cellular stress and
the initiation of apoptosis as these cells struggle to cope and respond to foreign junctional and adhesive
signaling networks [23-25] . Consequently, newly established micrometastatic lesions fail to propagate and
expand due to: (1) deficiencies to initiate and progress through the cell cycle; and (2) propensity to undergo
apoptosis at a pace that equals or exceeds the proliferative rate of DTCs. Despite these barriers, a subset of
DTCs remain viable and poised to reactivate proliferative programs that result in metastatic relapse years-
to-decades after implementation of initial treatments, such as chemotherapy and radical primary tumor
resection [26,27] . Clinically, extended periods of metastatic dormancy is evidenced by growth modeling studies
performed on over 1,000 breast cancer patients. In doing so, two discrete peaks that define the probability
of metastatic recurrence were identified: (1) one correlating with a model of continuous, slow growth of
metastatic cells; and (2) one corroborating the principle that the majority of delayed relapses are indeed the
[28]
result of a temporary period of dormancy prior to reactivation of proliferation programs . Indeed, it is
this second peak that poses the greatest threat to breast cancer patients, with ~62% of breast cancer deaths
[27]
occurring 5-20 years after initial diagnosis . Taken together, these findings reveal that dormant DTCs play
a pivotal role in the majority of breast cancer-associated mortality, a feature that cements them as one of the
most clinically relevant targets in all of oncology.

MODELS OF METASTATIC DORMANCY IN BREAST CANCER
In vitro and in vivo models of dormancy represent critical tools for investigating the molecular mediators
that impact dormant states. However, the establishment of such models pose significant challenges, as the
growth and propagation of dormant cell lines is, by definition, inherently impractical. Likewise, the size and
sparsity of dormant micrometastases makes their identification highly burdensome. Nonetheless, accepted
models of breast cancer dormancy do in fact exist. One particularly powerful model of metastatic dormancy