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Page 4 of 12 Flynn et al. J Cancer Metastasis Treat 2019;5:43 I http://dx.doi.org/10.20517/2394-4722.2019.13

Figure 2. Autophagy: a pro-survival strategy employed by breast cancer stem cells. One of the pro-survival strategies employed by breast
cancer stem cells during their acquisition of dormant states is autophagy, which facilitates the recycling of damaged or unnecessary
organelles and/or proteins as a means to provide energy during periods of metabolic stress. Upon initiation of autophagy, the phagophore
encircles those cellular contents targeted for autophagic degradation. LC3 is recruited to the phagophore and subsequently binds to
the cargo adaptor protein, p62/SQSTM1. Upon doing so, a double membrane structure called the autophagosome forms and encircles
cellular candidates for autophagic degradation. Subsequently, the autophagosome binds to the highly acidic lysosome to form the
autophagolysosome, wherein p62/SQSTM1 bound cellular contents are degraded

Figure 3. The tumor-suppressing and tumor-promoting activities elicited by autophagy. Autophagy functions to suppress tumor initiation
(left panel), as well as to promote tumor development and progression (right panel). In early stages of tumor formation or during periods
of metastatic dormancy, autophagy is tumor suppressive. Upon autophagy inhibition, p62/SQSTM1 accumulates and stabilizes Pfkfb3,
leading dormant breast cancer stem cells to initiate metastatic relapse. Additionally, p62/SQSTM1 also inhibits the interaction between
Keap1 and NRF2, thereby preventing NRF2-mediated expression of genes operant in tumor initiation (left panel). In stark contrast,
autophagy provides established tumors with pro-survival phenotypes, including protection from anoikis and intrinsic cellular stressors
encountered during metastatic dormancy. Likewise, autophagy protects breast cancer stem cells by ensuring for their resistance to the
apoptotic stimuli housed within the metastatic microenvironment (e.g., Src-mediated TRAIL resistance), and to chemotherapeutic insults
(e.g., Atg7-mediated p53 regulation of DNA repair). Finally, dormant cells can upregulate ARH1 to induce autophagy and promote the
activation of pro-survival signaling systems that ensure for their survival

deficient cells exhibit diminished homologous recombination (HR) repair of damaged DNA that arises due
to proteasomal degradation of checkpoint kinase 1 (Chk1) [45,46] . While non-homologous end joining (NHEJ)
appears to be largely unaffected by autophagy inhibition, the diminished HR proficiency in these cells can
render them more sensitive to DNA damage, especially if NHEJ is subsequently impaired [45,46] . Collectively,
these findings identify important mechanisms whereby autophagy functions to suppress malignant
transformation and tumor development.

AUTOPHAGY AND TUMOR PROMOTION
In contrast to its tumor suppressing functions, autophagy can also serve as a tumor promoting process,
particularly by: (1) enhancing the ability of DTCs to traverse the metastatic cascade; (2) inhibiting