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J Clin Invest. 2017 Dec 1;127(12):4498-4515. doi: 10.1172/JCI91553. Epub 2017 Nov 13.

JAK2-binding long noncoding RNA promotes breast cancer brain metastasis.

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
2
Department of Molecular Cell Biology and Toxicology, School of Public Health.
3
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, and.
4
State Key Laboratory of Reproductive Medicine, China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China.
5
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
6
Institute for Glycomics, Griffith University, Southport, Queensland, Australia.
7
Department of Gynecologic Oncology and Reproductive Medicine and.
8
Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
9
Department of Oncology, Yixing People's Hospital, Yixing, China.
10
Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
11
Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
12
Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA.
13
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
14
Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida, USA.
15
Department of Neurosurgery and.
16
Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Abstract

Conventional therapies for breast cancer brain metastases (BCBMs) have been largely ineffective because of chemoresistance and impermeability of the blood-brain barrier. A comprehensive understanding of the underlying mechanism that allows breast cancer cells to infiltrate the brain is necessary to circumvent treatment resistance of BCBMs. Here, we determined that expression of a long noncoding RNA (lncRNA) that we have named lncRNA associated with BCBM (Lnc-BM) is prognostic of the progression of brain metastasis in breast cancer patients. In preclinical murine models, elevated Lnc-BM expression drove BCBM, while depletion of Lnc-BM with nanoparticle-encapsulated siRNAs effectively treated BCBM. Lnc-BM increased JAK2 kinase activity to mediate oncostatin M- and IL-6-triggered STAT3 phosphorylation. In breast cancer cells, Lnc-BM promoted STAT3-dependent expression of ICAM1 and CCL2, which mediated vascular co-option and recruitment of macrophages in the brain, respectively. Recruited macrophages in turn produced oncostatin M and IL-6, thereby further activating the Lnc-BM/JAK2/STAT3 pathway and enhancing BCBM. Collectively, our results show that Lnc-BM and JAK2 promote BCBMs by mediating communication between breast cancer cells and the brain microenvironment. Moreover, these results suggest targeting Lnc-BM as a potential strategy for fighting this difficult disease.

KEYWORDS:

Breast cancer; Cell Biology; Oncology

PMID:
29130936
PMCID:
PMC5707156
DOI:
10.1172/JCI91553
[Indexed for MEDLINE]
Free PMC Article

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