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Page 4 of 14 Gooding et al. J Cancer Metastasis Treat 2019;5:41 I http://dx.doi.org/10.20517/2394-4722.2019.11

is the murine D2.HAN series, which consists of two cell lines that display distinct metastatic properties,
[29]
namely the dormant D2.OR cell line and the highly metastatic D2.A1 cell line . These cell lines were
derived from a premalignant murine hyperplastic alveolar nodule implanted into the cleared mammary fat
pad of BALB/c mice, resulting in spontaneous tumors that were subsequently classified by alternations in
[29]
their surface glycoprotein composition as determined by retention to the lectin, peanut agglutinin .

Accordingly, dormant D2.OR cells exhibit high affinity for peanut agglutinin and produce slow growing
tumors that are incapable of forming disseminated tumors in either spontaneous or experimental metastasis
models. In stark contrast, metastatic D2.A1 cells exhibit low affinity for peanut agglutinin and produce fast
[30]
growing tumors that metastasize aggressively . Importantly, in vivo videomicroscopy reveals that these
D2.HAN derivatives show no differences in the mechanism, timing, and proportion of cells capable of
extravasating into the lungs of mice, indicating that post-extravasation events underlie their vastly disparate
[31]
abilities to undergo metastatic outgrowth . Despite their inability to form secondary tumors, a large
proportion of disseminated D2.OR cells readily survive the process of extravasation (i.e., ~80% at 3 weeks
[32]
and ~50% at 11 weeks) and remain viable despite their non-proliferative phenotype (i.e., Ki-67-negative) .
Collectively, these cellular and functional features form the crux of the dormancy-associated phenotypes
exhibited by D2.OR cells in vivo, thus establishing them as a valuable model for studying the molecular
mechanisms underlying metastatic dormancy [33-35] .

lncRNAs in breast cancer
Elucidating the molecular determinants of breast cancer metastasis, especially those associated with DTC
acquisition of and eventual emergence from dormancy, remains a critical undertaking that is essential to
the future development of therapies capable of targeting DTCs. Recently, a surprising class of molecules
called long noncoding RNAs (lncRNAs) have been identified and function as potent contributors to the
malignant properties of breast cancer cells. Broadly, these transcripts are defined as RNA molecules that are
[36]
> 200 nucleotides in length and lack an open reading frame capable of producing a functional protein .
LncRNAs were originally believed to possess negligible function and exist primarily as “transcriptional
noise” originating from illegitimate regulatory DNA elements. However, it is now clear that lncRNA expression
patterns transpire in a highly specific cell- and tissue-dependent manner [37,38] . Importantly, noncoding RNA
molecules do not require protein-coding capacity to act as powerful determinants of cell fate. Indeed, lncRNAs
harbor immense intrinsic functionality within the course of cellular homeostasis and disease formation. For
instance, the developmental complexity of organisms correlates more closely with the extent and diversity of the
noncoding genome rather than with the collective composition of protein-coding genes [39-41] .

In light of the dynamic and diverse functions attributed to lncRNAs, it is unsurprising that malignant
cells, including those arising from the breast, have hijacked lncRNAs to directly and indirectly alter their
proliferative, invasive, and metastatic ability [42-44] . As such, several lncRNAs have been shown to modify
critical breast cancer-associated molecular pathways in a manner that transcends hormone receptor status,
[45]
frequently driving the development and progression of TNBCs . Similarly, ER-associated signaling
[46]
pathways also regulate the expression of lncRNAs , including HOTAIR, whose promoter contains several
[47]
estrogen response elements .
Moreover, induction of HOTAIR promotes the growth and metastasis of breast cancers via widespread
[48]
epigenetic reprogramming .
BORG
[49]
Although numerous lncRNAs have been linked to breast cancer tumorigenesis and metastasis , the
intergenic lncRNA BORG has recently emerged as a unique and formidable regulator of the metastatic
competence and survival of breast cancer cells. Originally discovered in murine C2C12 myoblast cells
treated with BMP2 or BMP7, BORG is a spliced and polyadenylated ~2.8 kb transcript that shows no