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Page 2 of 12 Flynn et al. J Cancer Metastasis Treat 2019;5:43 I http://dx.doi.org/10.20517/2394-4722.2019.13

node-negative and 70% of lymph node-positive breast cancer patients will eventually relapse 5-20 years
[3,4]
following initial diagnosis . The period of time between clinical remission and relapse can be attributed to
dormancy, a process whereby disseminated tumor cells (DTCs) enter a non-proliferative state coupled with
[5]
the activation of cellular stress programs . Even in the earliest stages of mammary tumor development,
breast cancer cells are actively shed from the growing tumor and traverse the metastatic cascade before
[6,7]
colonizing distant metastatic sites . These solitary micrometastases can persist in distant organs for years
or even decades before emerging as recurrent metastatic tumors. Indeed, experimental evidence and in silico
modeling indicate that dormant DTCs exist in a quiescent state as opposed to one that reflects a balance
between cell proliferation and apoptosis [8-12] . Dormant cells upregulate pro-survival factors and are inherently
chemoresistant given their non-proliferative state. As such, treatment with currently available therapeutics
does little to limit the population of dormant cells in breast cancer patients. In fact, ~62% of breast cancer-
[13]
associated deaths occur 5 years following diagnosis . As such, the clinical detection and treatment of these
recurrent metastases remains challenging due to: (1) difficulties in detecting growing lesions years or decades
following remission; (2) limited treatment options that are effective against metastatic disease [14,15] . Despite
the fact that systemic relapse following a period metastatic dormancy remains a large unmet clinical burden,
the precise mechanism(s) that enable dormant metastatic lesions to reactivate proliferative programs and
[3]
recur remains incomplete . Here we highlight the importance of breast cancer stem cells (BCSCs) and their
reliance upon autophagy to govern the activation and eventual emergence from metastatic dormancy, as well
as clinical implications of targeting autophagy therapeutically as a means to alleviate metastatic disease.

BCSCS AND METASTATIC DORMANCY: A ROUTE TO EVADE DETECTION AND

THERAPEUTIC ELIMINATION
Recent evidence suggests that DTCs endowed with the ability to survive metastatic dormancy and initiate
recurrent metastatic lesions are BCSCs [16-18] , which undergo unlimited self-renewal and contribute to tumor
[19]
initiation . Likewise, genomic analyses of primary and relapsed metastatic breast cancers reveal numerous
common driver mutations shared between primary and metastatic tumor lesions in a given patient. As such,
these common mutational landscapes implicate the presence of a common malignant cell of origin and
support the notion that disseminated BCSCs initiate recurrent metastatic lesions years or decades following
clinical remission [20-23] . This process reflects the ability of BCSCs to adopt dormancy-associated phenotypes
through several malleable events, including modulation of E-cadherin and lncRNA expression [24,25] . Equally
important facets of metastatic relapse are the capacity of BCSCs to evade immune surveillance and resist
therapeutic interventions aimed at eradicating residual disease. Amongst the pro-survival strategies
activated by BCSCs are: (1) upregulated expression of ATP-binding cassette transporters that mediate
cellular efflux of chemotherapeutic agents [26-28] ; (2) increased production of Interleukin-4 (IL-4) to suppress
[30]
[29]
apoptosis ; (3) enhanced generation of reactive oxygen species in response to radiation ; (4) elevated
activation of autophagy [16-18,31] [Figure 1]. As such, dormant BCSCs are inherently resistant to traditional
chemotherapeutic agents and radiation that target rapidly dividing tumor cells. In the succeeding sections,
we highlight the role of autophagy in regulating mammary tumorigenesis and dormancy-associated
phenotypes during metastatic progression and relapse.

CONTEXT-DEPENDENT ROLE OF AUTOPHAGY IN TUMOR PROGRESSION
Macroautophagy (hereafter referred to as autophagy) is a highly conserved process that maintains cellular
homeostasis through the lysosomal degradation of proteins and organelles, a phenomenon that is tightly
[32]
controlled by autophagy-related genes (ATGs) . The autophagosome cargo protein, p62/sequestosome 1
[33]
(SQSTM1), binds to degradation targets and facilitates selective autophagy . Indeed, during the activation
of autophagy, ATGs mediate the recycling of p62/SQSTM1-tagged cargo through the formation of double-
membrane vesicles, termed autophagosomes, which fuse with lysosomes to form autophagolysosomes.
Lysosomal fusion facilitates the degradation of nonfunctional cellular components and also functions