JAK2-binding long noncoding RNA promotes breast cancer brain metastasis.
Journal Article (Journal Article)
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.
- Wang, S; Liang, K; Hu, Q; Li, P; Song, J; Yang, Y; Yao, J; Mangala, LS; Li, C; Yang, W; Park, PK; Hawke, DH; Zhou, J; Zhou, Y; Xia, W; Hung, M-C; Marks, JR; Gallick, GE; Lopez-Berestein, G; Flores, ER; Sood, AK; Huang, S; Yu, D; Yang, L; Lin, C
- December 1, 2017
Volume / Issue
- 127 / 12
Start / End Page
- 4498 - 4515
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)
- United States