Abstract
Although greater than 90% of breast cancer-related mortality can be attributed to metastases, the molecular mechanisms underpinning the dissemination of primary breast tumor cells and their ability to establish malignant lesions in distant tissues remain incompletely understood. Genomic and transcriptomic analyses identified a class of transcripts called long noncoding RNA (lncRNA), which interact both directly and indirectly with key components of gene regulatory networks to alter cell proliferation, invasion, and metastasis. We identified a pro-metastatic lncRNA BORG whose aberrant expression promotes metastatic relapse by reactivating proliferative programs in dormant disseminated tumor cells (DTCs). BORG expression is broadly and strongly induced by environmental and chemotherapeutic stresses, a transcriptional response that facilitates the survival of DTCs. Transcriptomic reprogramming in response to BORG resulted in robust signaling via survival and viability pathways, as well as decreased activation of cell death pathways. As such, BORG expression acts as a (i) marker capable of predicting which breast cancer patients are predisposed to develop secondary metastatic lesions, and (ii) unique therapeutic target to maximize chemosensitivity of DTCs. Here we review the molecular and cellular factors that contribute to the pathophysiological activities of BORG during its regulation of breast cancer metastasis, chemoresistance, and disease recurrence.
Highlights
With over 250,000 newly diagnosed cases in 2017, breast cancer is the most commonly diagnosed malignancy among U.S women[1]
From a potential clinical perspective, aberrant BMP/OP-Responsive Gene (BORG) expression is most frequently associated with triple-negative breast cancer (TNBC)/ basal-like breast cancers, as determined by scrutinizing several publicly available RNA-seq datasets
Malignant tissues clearly express increased levels of BORG as compared to normal human mammary epithelial cells[56,57]. These findings support the hypothesis that primary malignancies that house high levels of BORG will disperse aggressive breast cancer cells that are predisposed to establishing clinically-relevant, chemoresistant secondary lesions
Summary
With over 250,000 newly diagnosed cases in 2017, breast cancer is the most commonly diagnosed malignancy among U.S women[1]. Expression of a dominant-negative IκBa in TNBCs prevented their expression of BORG following exposure to doxorubicin, and to environmental stresses, such as hypoxia and nutrient deprivation[56] 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. 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 associated with the acquisition of metastatic and chemoresistant phenotypes[90,91,92,93], upon their colonization of foreign tissue microenvironments[94]. 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
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