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Page 10 of 14 Gooding et al. J Cancer Metastasis Treat 2019;5:41 I http://dx.doi.org/10.20517/2394-4722.2019.11

Figure 1. BORG is a potent facilitator of breast cancer metastasis. Breast cancer cells can disseminate at very early stages of development.
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Due to the benign microenvironment associated with these lesions, these cells are likely to harbor low levels of BORG (BORG )
expression and are prone to establishing dormant lesions in metastatic tissues. Nonetheless, stromal factors and environmental stressors
in the metastatic microenvironment can induce BORG expression, thereby compelling these dormant cells to reinstate proliferative
programs. The progression of primary tumors is associated with a hypoxic environment and stark competition for nutrients. Such stresses
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can enhance BORG expression in a subset of cells (BORG ). These BORG cells can disseminate to distant tissues where they exploit the
proliferative and survival advantages afforded by BORG to produce overt metastases. Cytotoxic chemotherapeutic treatment is effective
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against BORG cells, but BORG cells show resistance to such therapies and are the foundation for chemoresistant, residual disease that
can eventually metastasize to distant tissues. BORG: BMP/OP-Responsive Gene
hypoxic and metabolic stresses associated with the metastatic microenvironment, can lead to the induction
of BORG expression within these dormant DTCs, thereby activating proliferative programs and survival
signaling to promote their metastatic outgrowth [Figure 1].

Finally, neoadjuvant or adjuvant treatment of primary breast cancers with chemotherapeutic agents (e.g.,
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doxorubicin) will selectively kill BORG cells that are not inherently resistant to the cytotoxic effects of these
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agents. The residual, chemoresistant BORG cells can subsequently contribute to the recurrence of metastatic
or primary lesions that are insensitive to standard-of-care therapies [Figure 1]. These diverse cellular
outcomes downstream of BORG establish this lncRNA as an essential driver of breast cancer metastasis and
highlight the potential utility derived from therapeutically targeting BORG or its effectors as a novel means
to alleviate the metastatic outgrowth and recurrence of disseminated TNBCs.