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Page 2 of 14 Gooding et al. J Cancer Metastasis Treat 2019;5:41 I http://dx.doi.org/10.20517/2394-4722.2019.11

Keywords: BORG, chemoresistance, disease recurrence, dormancy, long noncoding RNA, metastasis, triple-negative
breast cancer

INTRODUCTION
With over 250,000 newly diagnosed cases in 2017, breast cancer is the most commonly diagnosed
[1]
malignancy among U.S. women . Although recent advances in treatment have produced a moderate decline
[2]
in the mortality rate associated with breast cancer , this disease nevertheless still plagues women and is
[1]
the second leading cause of cancer-related death, resulting in over 40,000 deaths each year . The clinical
management of breast cancer is complicated by its manifestation as an exceptionally heterogeneous disease.
In fact, the degree of molecular and histopathologic variation demonstrated by breast cancers necessitates
its classification not as a single, uniform disease, but rather as one that is composed of a diverse collection
of diseases that possess varying clinical prognoses and require distinct treatment strategies. Integral to this
heterogeneity are the receptors for the ovarian steroid hormones estrogen (ER) and progesterone (PR), and
for the membrane-associated tyrosine kinase HER2/ErbB-2. Moreover, the expression or lack thereof of
[3,4]
these receptors dictates therapeutic schemes and disease-free progression . Likewise, the multiple various
permutations in the expression patterns of these receptors exemplify the heterogeneity of the disease and
necessitate the tailoring of specific treatments to each individual patient. In fact, clinicopathologic detection
for the expression of these receptors remains an advantageous trait, as they represent some of the most
[5]
consistently predictive and actionable molecular targets in all of oncology . As such, the largest clinical
burden associated with breast cancer stems from a subset of patients whose tumors fail to express ER, PR,
and HER2, lesions known as triple-negative breast cancer (TNBC). This genetically distinct breast cancer
[6]
subtype constitutes ~15%-20% of all diagnosed breast cancers and portends the worst overall survival rates
of all breast cancer subtypes, an untoward trait that reflects their extreme propensity to relapse within 5
[7]
years of initial diagnosis and treatment . The molecular features that underlie the development, metastasis,
and relapse of TNBCs remain to be fully elucidated. Recently, a novel intergenic lncRNA known as BMP/
OP-Responsive Gene (BORG) was identified as being a prominent driver of these tumorigenic activities
in TNBCs. Here we highlight the pathophysiology associated with aberrant BORG expression in TNBCs,
as well as discuss clinical implications of BORG and its potential for therapeutic targeting to alleviate
metastatic disease.

Breast cancer metastasis
Despite immense efforts undertaken to characterize the molecular complexity of primary breast cancers,
the lethality associated with all subtypes of breast cancer is attributed primarily to the dissemination
[8,9]
and colonization of distant tissues , an untoward clinical event that results in dismal median survival
rates of ~1 year. Moreover, the finding of metastatic TNBC is essentially a fatal diagnosis regardless of the
[10]
chemotherapeutic intervention deployed to combat this disease . Despite decades of intense investigation,
a complete understanding of the molecular forces vital to metastasis remains incomplete, a knowledge gap
that continues to hinder the development of therapeutics capable of specifically targeting and alleviating
metastatic lesions. Nonetheless, fundamental steps taken by malignant cells to facilitate their dissemination
from the primary tumor site to distant tissues for colonization have been identified and are called the
[11]
metastatic cascade . The events that comprise this multi-step process include: (1) local invasion and
migration of malignant cells into the stroma surrounding the primary lesion; (2) intravasation into the
vasculature or lymphatic system to permit transit through these circulatory routes; (3) vascular stasis
and subsequent extravasation into parenchymal tissues at distant sites of colonization; (4) survival and
[12]
micrometastasis formation; and (5) overt growth and metastasis formation . Interestingly, the earliest
phases of metastatic progression (i.e., dissociation and emigration from site of origin via the vasculature)
represent the barriers that are most easily surmounted by primary lesions, as evidenced by the fact that
tumors readily liberate thousands upon thousands of cells into the circulation each day [13,14] . However,