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Flynn et al. J Cancer Metastasis Treat 2019;5:43 I http://dx.doi.org/10.20517/2394-4722.2019.13 Page 9 of 12

highly ineffective at restoring endocrine sensitivity to estrogen receptor-positive breast cancers. Likewise,
combining autophagy modulators with anti-estrogens has also failed to significantly improve the clinical
[80]
course of these patients, with severe toxicities being associated with Everolimus . Thus, similar to the
strategy of autophagy inhibition, the clinical utility of autophagy activation to eliminate metastatic breast
cancers awaits additional mechanistic and translational investigation.

CONCLUSION
Metastatic dormancy is mediated by BCSCs and responsible for the majority of breast cancer-associated
deaths. An inherent property of BCSCs reflects their ability to activate a variety of pro-survival strategies
to circumvent metabolic stress within the metastatic niche, and to overcome therapeutic insults mediated
by chemotherapies and radiation. The activation of autophagy has proven to be a critical component of the
pro-survival strategies employed by BCSCs, especially when confronted with nutrient deprivation, with
inhospitable tissue microenvironments, with cytotoxic agents, and with dormancy-associated phenotypes.
Indeed, preclinical evidence implicates important roles for autophagy modulation in the treatment of breast
cancer. However, the paradoxical functions of autophagy to both suppress and promote tumorigenesis has
clearly hampered the development and implementation of effective autophagy modulators for the treatment
of metastatic breast cancer. Accordingly, several important avenues of basic and clinical investigation need
to be achieved in order to generate effective autophagic agents. First, studies need to determine the extent
to which chemotherapeutic drugs rely upon autophagy modulation when inducing their cytotoxic activities
in target cells. Indeed, these so-called “off-target” effects on autophagy may underscore either directly or
indirectly the extent to which a therapeutic regimen is effective, or alternatively, is rendered insensitive.
Second, additional efforts need to be directed at identifying improved autophagy modulating drugs,
particularly those that are effective against metastatic disease. Third, enhancing our understanding of how
the tumor microenvironment impacts the targeting of autophagy-directed drugs is also warranted [84-86] .
Finally, efforts directed at developing biomarkers capable of identifying patients most likely to benefit from
autophagy modulation needs to be undertaken to minimize potential untoward side effects (e.g., disease
progression, emergence from dormancy, and metastatic relapse) of this course of treatment. Ultimately,
addressing these research avenues will provide new inroads for strategies aimed at targeting autophagy
vulnerability in BCSCs, and consequently, at eliminating metastatic relapse.

DECLARATIONS
Acknowledgments
Members of the Schiemann Laboratory are thanked for critical comments and reading of the manuscript.

Author’s contributions
Conception and study design: Flynn ALB, Schiemann WP
Drafted and revised the manuscript: Flynn ALB, Schiemann WP

Availability of data and materials
Not applicable.

Financial support and sponsorship
Research support was provided in part by the National Institutes of Health (CA236273) to Schiemann
WP, and (T32GM008803 and T32CA059366) to Flynn ALB. Additional support was graciously provided
by the METAvivor Foundation to Schiemann WP, and by pilot funding from the Case Comprehensive
Cancer Center’s Research Innovation Fund, which is supported by the Case Council and Friends of the
Case Comprehensive Cancer Center to Schiemann WP, and from the Case Clinical & Translational Science
Collaborative to Schiemann WP.