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Page 6 of 14 Gooding et al. J Cancer Metastasis Treat 2019;5:41 I http://dx.doi.org/10.20517/2394-4722.2019.11

tertiary structure interactions with DNA [41,65] . Along these lines, chromatin immunoprecipitation assays
[57]
reveal that BORG enhances the binding of TRIM28 to specific genomic loci . Thus, BORG promotes
the metastatic outgrowth of dormant DTCs in part through its ability to promote the localization and
transcriptional repressive activity of TRIM28. Although BORG directly modifies the ability of TRIM28 to
suppress the expression of p21 and gadd45a in dormant DTCs, it should be noted that TRIM28 also exerts
widespread alterations in the transcriptomes of a multitude of cell types [63,64,66] . To gain additional insight
into the repertoire of transcriptional events coupled to TRIM28 in DTCs, we performed RNA-seq and
microarray-based transcriptomic analyses on parental and BORG-expressing D2.OR organoids propagated
in 3D-cultures. To assess the specific impact of TRIM28 on these dormancy-associated phenotypes (i.e.,
parental dormancy vs. BORG-mediated outgrowth), we also rendered these cells deficient in TRIM28
expression. Unsurprisingly, BORG-expressing D2.OR cells harbored a transcriptional signature that
deviated significantly from its parental and TRIM28-deficient counterparts. Moreover, cellular network
analyses revealed specific BORG- and TRIM28-dependent transcriptional patterns that were significantly
[57]
enriched for proliferative and pro-metastatic signatures . Collectively, these findings establish BORG as the
only known lncRNA that functions in modifying the activity and cellular localization of a transcriptional
regulator (i.e., TRIM28) to confer genome-wide transcriptomic alterations that compel the reactivation of
proliferative programs in dormant DTCs.

Chemoresistance
The development of therapeutic resistances continues to hamper the prolonged efficacy of standard-of-care
treatment regimens. Moreover, these clinical challenges are compounded by the fact that the underlying
mechanisms responsible for targeted and chemotherapeutic resistance are immensely diverse. Nonetheless,
malignant breast cancer cells regularly rely on the malleable intrinsic state of cancer cells, which enables
[67]
their adaptation to cytotoxic cellular stresses in order to maintain viability in a manner that most
[68]
closely follows the paradigm of acquired resistance . Indeed, the plasticity underlying the appearance of
chemoresistance is naturally permissive and reflects alterations in the epigenome. Moreover, these events are
bolstered by defects in the ability of DTCs to maintain genome integrity that arise in response to aberrant
cell cycle checkpoints and DNA repair mechanisms, and to increased rates of proliferation. Additionally,
interactions between DTCs and the tumor microenvironment induce unique de novo mechanisms of
therapeutic resistance, as cell adhesion networks (e.g., integrins) activate a specialized survival program
known as “cell adhesion-mediated” drug resistance that elicit DTC insensitivity to numerous treatment
regimens [69,70] . As such, the stromal composition of the metastatic microenvironment creates a natural
sanctuary for DTCs to survive therapeutic insults.

Interestingly, dormant DTCs have long been recognized for their inherent resistance to commonly used
[11]
chemotherapeutic drugs . These resistant traits naturally stem from the quiescent phenotype of dormant
cells, which effectively abolishes the clinical utility of chemotherapeutics and cytotoxic agents that target
[71]
metabolically active and dividing cells . Moreover, dormant cells preferentially upregulate signaling
pathways associated with cell survival, a trait stemming from their allocation of metabolic resources
away from cell cycle progression as a means to remain viable in the face of environmental stressors (i.e.,
[72]
chemotherapy) . Accordingly, chemotherapeutic treatment can select for a subset of dormant cells that
are enriched for pro-survival pathways and multidrug resistance, implying that cytotoxic insults can select
for a population of cells that are exceedingly equipped to instigate post-therapy relapse [73,74] . Importantly,
we recently determined that BORG plays a central role in driving the development of chemoresistance in
TNBCs (see below).

BORG: a novel inducer of chemoresistance
In addition to possessing enhanced proliferative abilities, BORG-expressing D2.OR cells also exhibit: (1)
extensive upregulation of pro-survival and viability pathways; and (2) widespread downregulation of cell