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immunosurveillance by tumor infiltrating immune cells. During metastasis, cells shed from the primary
tumor must invade through the extracellular matrix, intravasate into blood vessels, survive the turbid
[47]
flow of the vasculature, extravasate, and finally colonize a distant metastatic site . Not surprisingly,
cells traversing the metastatic cascade experience a variety of cellular stressors and vastly different tissue
microenvironments, including changes in the (1) composition of the extracellular matrix composition;
(2) availability of nutrients due to alterations in vascular and lymphatic networks; (3) biomechanical
properties of metastatic sites; (4) tumor immunosurveillance programs [48-50] . Importantly, autophagy
activation protects DTCs during periods of metabolic stress encountered by anoikis and entry into foreign
microenvironments [51-53] , and by bouts of dormancy at distant metastatic sites [54,55] .

AUTOPHAGY INHIBITS TUMOR IMMUNOSURVEILLANCE
Tumor immunosurveillance is a critical physiological process that inhibits the development and progression
of mammary tumors. Accumulating data in the literature indicate that tumor immunosurveillance programs
are an all-encompassing system that involves not only the adaptive immune system and cytotoxic effector
pathways, but also the release of a complex set of cytokines and chemokines that coalesce to prevent tumor
[50]
development . Although the molecular mechanisms used by tumor cells to escape immunosurveillance
are varied, recent evidence has implicated a role for autophagy in mediating this phenomenon. Indeed,
autophagy activation has been shown to inhibit immune cell killing of tumor cells as a means to promote
[50]
escape from immunosurveillance and DTC outgrowth . In doing so, autophagy activation can target the
activation of Signal Transducer and Activator of Transcription 3 (STAT3), a gene commonly dysregulated
[56]
in breast cancer that also plays a prominent role in regulating the immune system . For instance, the
activation of autophagy can induce the phosphorylation and stimulation of STAT3 in tumors, an event
that initiates cellular cross-talk between tumor and immune cells that ultimately suppresses Cytotoxic T
Lymphocyte (CTL)-mediated lysis of tumor cells [56,57] . Likewise, autophagy can inhibit natural killer cell
(NK)-mediated tumor cell killing by degrading granzyme B, a serum protease that is released by NK cells
during NK-mediated cell killing [58,59] . Finally, breast cancer development and metastatic progression is
[60]
critically dependent upon Epithelial-Mesenchymal Transition (EMT) programs . Interestingly, autophagy
is activated as carcinoma cells traverse the EMT program, with the resulting post-EMT mesenchymal-
like cells exhibiting elevated levels of autophagy relative to their pre-EMT epithelial-like counterparts.
Importantly, EMT-mediated activation of autophagy inhibits CTL-mediated antitumor immunosurveillance
in a beclin-1-dependent manner [50,61-63] . Collectively, these studies highlight the tumor intrinsic and extrinsic
functions of autophagy, with the latter function, fulfilling an essential role in governing the fidelity of tumor
immunosurveillance mechanisms.

DORMANT BCSCS AND AUTOPHAGY ACTIVATION
BCSCs can lie dormant for decades before recurring as metastatic lesions in breast cancer patients. During
this time, disseminated BCSCs must survive nonpermissive tumor environments, while simultaneously
maintaining their viability and the capacity for tumor initiation [5,64] . Emerging evidence implicates autophagy
as an essential feature in maintaining the phenotypes associated with BCSCs, particularly their resistance to
chemotherapies and hypoxic microenvironments [16,18,54,55,65-67] . The mechanisms whereby autophagy promotes
BCSC survival at metastatic sites are varied and include the ability to confer resistance to apoptotic stimuli
[68]
(e.g., Src-mediated TRAIL resistance in bone metastases ), to chemotherapeutic insults (e.g., DNA repair
[69]
[70]
via Atg7 and p53 by Atg7 ), and to cellular stressors . Similarly, aberrant expression of ARHI (aplasia
Ras homolog member 1) can elicit autophagy activation and modulate the survival of dormant cells in
preclinical models of ovarian cancer, further implicating autophagy as an essential mediator of dormant cell
[71]
survival . Finally, tumor cells that possess defects in autophagy readily accumulate p62/SQSTM1, an event
[17]
that alters p62/SQSTM1 function and contributes to tumorigenesis . The aforementioned studies highlight
the oncogenic and pro-survival activities of autophagy that contribute to tumor progression, as well as the