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The lncRNA BORG facilitates the survival and chemoresistance of triple-negative breast cancers

Oncogene volume 38, pages 2020–2041 (2019)Cite this article

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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.

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Data availability

All sequencing data provided herein have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) and can be accessed through the GEO Series accession number GSE116656. All additional data are available from the corresponding authors upon request.

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Acknowledgements

Members of the Schiemann Laboratory are thanked for critical comments and reading of the manuscript. We thank Dr. Ricky Chan for assistance in our analyses of RNA-seq data. We also acknowledge the expertise provided by members of the Case Comprehensive Cancer Center’s Core Facilities, including the Gene Expression & Genotyping Core, the Imaging Research Core, Tissue Resources Core, and the Genomics Core. Research support was provided in part by the National Institutes of Health to W.P.S. (CA129359, CA177069, and CA194518) and A.J.G (T32GM007250 and F30CA203233). Additional support was graciously provided by the METAvivor Foundation (W.P.S.), and by pilot funding from the Case Comprehensive Cancer Center’s Research Innovation Fund, which is supported by the Case Council and Friends of the Case Comprehensive Cancer Center (W.P.S. and S.V.).

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  1. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA

    Alex J. Gooding, Abigail Beard & William P. Schiemann

  2. Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, 44106, USA

    Bing Zhang, Lalith Gunawardane & Saba Valadkhan

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  1. Alex J. Gooding
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A.J.G., S.V. and W.P.S. conceived and designed the study, as well as interpreted the findings. A.J.G. carried out the molecular, cellular, and in vivo analyses with assistance from B.Z., L.G, and A.B. A.J.G. drafted the manuscript, which was revised and edited by A.J.G., S.V. and W.P.S. All authors read, commented, and approved the final version of the manuscript.

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Correspondence to Saba Valadkhan or William P. Schiemann.

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Gooding, A.J., Zhang, B., Gunawardane, L. et al. The lncRNA BORG facilitates the survival and chemoresistance of triple-negative breast cancers. Oncogene 38, 2020–2041 (2019). https://doi.org/10.1038/s41388-018-0586-4

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