Abstract
Disseminated breast cancer cells employ adaptive molecular responses following cytotoxic therapeutic insult which promotes their survival and subsequent outgrowth. Here we demonstrate that expression of the pro-metastatic lncRNA BORG (BMP/OP-Responsive Gene) is greatly induced within triple-negative breast cancer (TNBC) cells subjected to environmental and chemotherapeutic stresses commonly faced by TNBC cells throughout the metastatic cascade. This stress-mediated induction of BORG expression fosters the survival of TNBC cells and renders them resistant to the cytotoxic effects of doxorubicin both in vitro and in vivo. The chemoresistant traits of BORG depend upon its robust activation of the NF-κB signaling axis via a novel BORG-mediated feed-forward signaling loop, and via its ability to bind and activate RPA1. Indeed, genetic and pharmacologic inhibition of NF-κB signaling or the DNA-binding activity of RPA1 abrogates the pro-survival features of BORG and renders BORG-expressing TNBCs sensitive to doxorubicin-induced cytotoxicity. These findings suggest that therapeutic targeting of BORG or its downstream molecular effectors may provide a novel means to alleviate TNBC recurrence.