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Page 8 of 14 Gooding et al. J Cancer Metastasis Treat 2019;5:41 I http://dx.doi.org/10.20517/2394-4722.2019.11

Interestingly, the promoter region of the BORG locus contains multiple stretches of nucleotides that exhibit
sequence homology to the consensus DNA-binding sequence for NF-kB. Accordingly, NF-kB readily bound
to the BORG promoter in BORG-expressing cells, thereby identifying a novel feed-forward loop whereby
the activation of NF-kB (i.e., through chemotherapeutic and environmental stressors [86-89] ) leads to enhanced
BORG expression, which further promotes the induction NF-kB responsive genes. Along these lines,
expression of a dominant-negative IkBa in TNBCs prevented their expression of BORG following exposure
[56]
to doxorubicin, and to environmental stresses, such as hypoxia and nutrient deprivation . Collectively,
these findings implicate BORG as a unique lncRNA that is capable of promoting a NF-kB feed-forward
signaling loop that effectively links metastasis-associated cellular stresses to a coordinated signaling program
that engenders the survival of disseminated TNBCs.

BORG and breast cancer stem cells
Breast cancer stem cells (BCSCs) are malignant cells capable of tumor initiation, self-renewal, and
differentiation into a heterogeneous group of cancer cells that reflect those present in the original primary
breast tumor; they are also associated with the acquisition of metastatic and chemoresistant phenotypes [90-93] ,
[94]
particularly upon their colonization of foreign tissue microenvironments . BCSCs typically divide
asymmetrically to create: (1) a single progenitor cell capable of differentiating into a variety of functionally
diverse cancer cell types; and (2) a single BCSC that can expand and undergo continual self-renew. Attempts
to characterize BCSCs has been hampered by a relative lack of universal markers for BCSCs [95,96] . Indeed,
+
BCSCs have been linked to the expression of several cell surface proteins, such as CD133 and CD44 /CD24 -
, and to the intracellular protein, ALDH1 [97-99] . Recent findings have associated the expression of lncRNAs
with the generation and expansion of BCSCs. For instance, the lncRNAs ROR, HOTAIR, and Hh all induce
the expression of transcription factors that regulate “stemness”, such as SOX2 and OCT4; they also impact
the initiation of EMT programs [100-103] , which elicit the selection, expansion, and self-renewal of BCSCs [104] .
The role of BCSCs in regulating metastasis, chemoresistance, and survival signaling are reminiscent of the
features attributed to aberrant BORG expression, suggesting that BORG may also regulate the behaviors
of BSCSs. Accordingly, BORG expression is elevated significantly in BCSCs as compared to non-BCSCs
populations; it also enhances the mammosphere forming activity of human and murine breast cancer cells
(Gooding et al. [56,57] , unpublished observation). Thus, future studies need to determine precisely how BORG
impacts the transcriptomic and epigenetic landscapes of breast cancer cells to impart BCSC characteristics
coupled to metastatic progression and disease recurrence.

DISCUSSION AND CLINICAL IMPLICATIONS OF BORG
Metastasis is an exceedingly complicated process, whereby tumor cells must undergo coordinated efforts
to successfully disperse from primary tumors, emigrate to distant tissues, and survive and colonize
foreign microenvironments. Even for highly transformed cells, traversing the metastatic cascade is
[15]
immensely challenging, with the vast majority of disseminated cells unable to form overt metastases . The
inefficiencies characterizing metastasis are predominantly attributed to the cellular stresses associated with
unfamiliar metastatic microenvironments, forces that obstruct both the survival and outgrowth of DTCs.
Accordingly, BORG has emerged as a potent and unique lncRNA that is poised to enhance breast cancer
metastasis by altering both sides of this equation, i.e., providing both proliferative and pro-survival stimuli
to DTCs.

From a potential clinical perspective, aberrant BORG expression is most frequently associated with TNBC/
basal-like breast cancers, as determined by scrutinizing several publicly available RNA-seq datasets.
Moreover, we detected significant elevations of BORG in metastatic human patient-derived xenograft
tissue samples, and in CNS metastases and their matched primary tumors from which these metastatic
foci derived. In all cases, malignant tissues clearly express increased levels of BORG as compared to
normal human mammary epithelial cells [56,57] . Thus, these findings support the hypothesis that primary