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Gooding et al. J Cancer Metastasis Treat 2019;5:41 I http://dx.doi.org/10.20517/2394-4722.2019.11 Page 9 of 14

malignancies that house high levels of BORG will disperse aggressive breast cancer cells that are predisposed
to establishing clinically-relevant, chemoresistant secondary lesions. Indeed, TNBC patients who succumbed
to metastatic relapse within 5 years of initial diagnosis and treatment possessed primary tumors that
contained significantly higher levels of BORG compared to primary tumors derived from TNBC patients
[57]
who remained disease-free for at least 5 years post-treatment . Taken together, these intriguing findings
suggest that quantifying BORG expression in primary tumors could offer important insights into predicting
the natural and clinical course of breast disease within TNBC patients.

The correlative finding that BORG expression largely aligns with the overall malignant propensity of breast
cancer cells fails to address the mechanisms and signaling systems ultimately coupled to its upregulation
in developing mammary tumors. Indeed, it has been proposed that lncRNAs evolved as a means to assist
in maintaining cellular homeostasis in response to a wide variety of pathophysiologic conditions [105] .
Accordingly, we show that BORG expression is similarly influenced by a number of cellular stressors,
[56]
including chemotherapeutic insult, nutrient deprivation, and hypoxia , as well as in response to heat shock
[56]
(Gooding et al. and Valadkhan et al. [105] , unpublished observation). Moreover, NF-kB is critical in linking
[56]
the responsiveness of BORG to these environmental stressors , as NF-kB activation has long been tied to
the survival of cells confronted with a host of intrinsic and extrinsic stressors [84,85,106] . It therefore stands to
reason that increased flux through the NF-kB pathway stemming from exposure to noxious stimuli may
serve as the initial impetus in triggering the aforementioned NF-kB feed-forward loop, wherein NF-kB-
[56]
induced upregulation of BORG propagates expression of NF-kB-responsive gene expression patterns .

Tumor progression and metastatic competence are thought to rely heavily upon the intrinsic plasticity of
malignant cells, which facilitates their adaptation to harsh foreign microenvironments in order to maintain
viability [67,107] . Because BORG is largely regulated by extracellular paracrine factors (e.g., TGF-b, BMP-2, and
BMP-7 [50,56] ) and the environmental cues, we surmise that BORG acts as a context-dependent, transcriptional
rheostat for disseminated breast cancer cells, thereby dictating their engagement of proliferative and pro-
survival pathways. Indeed, when faced with environmental or therapeutic stresses, the induction of BORG
in malignant cells orchestrates a transcriptional signature that provokes aggressive tumorigenic states
that ensures for their survival. As such, preventing BORG expression or impeding the activation of its
downstream targets represents an innovative and potentially impactful strategy to target metastatic breast
cancers and drive them into an apoptosis-prone state.

Current mechanistic insights into the regulation of BORG and its downstream effectors reveal that this
lncRNA is uniquely poised to promote the metastasis of breast cancer cells. Indeed, BORG clearly exerts
a pro-metastatic effect at both the primary and metastatic sites of tumor growth. For example, a subset of
hi
breast cancer patients may harbor primary tumor cells that have gained the expression of BORG (BORG )
as a result of environmental stresses associated with a growing primary tumor (i.e., hypoxia and nutrient
deprivation; Figure 1). Such tumors are prone to shedding BORG cells into the circulation that disseminate
hi
to distant tissues, wherein they exploit the proliferative and pro-survival effects of BORG to overcome the
hostile metastatic microenvironment and form overt metastases [Figure 1]. Accordingly, and as noted
above, TNBC patients who succumbed to metastatic relapse within 5 years of initial diagnosis and treatment
possessed primary tumors that contained significantly higher levels of BORG compared to primary tumors
derived from TNBC patients who remained disease-free for at least 5 years post-treatment. Furthermore,
[18]
breast cancer cells can emigrate from the primary tumor at very early stages of tumor development .
As such, these early disseminated breast cancer cells are likely to originate from a lesion experiencing
little hypoxic or metabolic stress and are therefore more prone to harboring low levels of BORG (BORG ).
lo
lo
Although still capable of disseminating to distant tissues, these BORG cells are predicted to struggle
within their foreign microenvironments, resulting in their undergoing cell death or retreating into a state of
metastatic dormancy. Nonetheless, stromal paracrine signals (e.g., TGF-b, BMP2, or BMP7), as well as the