Editors' ChoiceCancer

A “LINK” in triple-negative breast cancer

Sci. Signal.  09 Feb 2016:
Vol. 9, Issue 414, pp. ec24
DOI: 10.1126/scisignal.aaf4266

Treatment options are limited for triple-negative breast cancer (TNBC), in which the cells lack the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that is normally stabilized and active only under hypoxic conditions, when it promotes angiogenesis, enhances survival, and triggers metabolic reprogramming. Lin et al. found the long noncoding RNA (lncRNA) LINK-A (long intergenic noncoding RNA for kinase activation) mediated a signaling pathway that resulted in the aberrant stabilization of HIF-1α under normal oxygen conditions in TNBC. LINK-A abundance was greater in TNBC tissues than in adjacent normal tissues or in single- or double-negative tumors. Unlike many lncRNAs, LINK-A was localized mainly to the cytoplasm, where it indirectly associated with HIF-1α, as well as with epidermal growth factor receptor (EGFR) and the transmembrane glycoprotein GPNMB, receptors that promote the progression and metastasis of TNBC. In addition, LINK-A directly associated with breast tumor kinase (BRK) and leucine-rich repeat kinase 2 (LRRK2). In MDA-MB-231 cells, a TNBC cell line, exposure to heparin-binding epidermal growth factor (HB-EGF) induced the heterodimerization of EGFR and GPNMB and the phosphorylation of EGFR, GPNMB, BRK, and HIF-1α. Upon stimulation with HB-EGF, EGFR phosphorylated Tyr525 in GPNMB, which promoted the interaction of EGFR and GPNMB and the subsequent phosphorylation of Tyr351 in BRK and activation of this kinase. LINK-A recruited BRK to the EGFR-GPNMB heterodimer and promoted a conformational change in BRK that enabled phosphorylation of Tyr351. BRK phosphorylated HIF-1α at Tyr565, a phosphorylation event that prevented the prolyl hydroxylation of HIF-1α, a posttranslational modification that triggers its degradation under normoxic conditions. LRRK2 phosphorylated Ser797 in HIF-1α, which enhanced the interaction of HIF-1α with the transcriptional coactivator p300. In normoxic MDA-MB-231 cells, HB-EGF stimulated the transcription of HIF-1α target genes. Knockdown of LINK-A in MDA-MB-231 cells impaired the transcriptional activity of HIF-1α and suppressed xenograft growth in mice. Samples from TNBC patients had increased phosphorylation of GPNMB, BRK, and HIF-1α at both Tyr565 and Ser797, which correlated with shorter survival. These results not only uncover an HB-EGF–induced signaling pathway mediated by protein interactions with a lncRNA but also reveal potential therapeutic targets for TNBC.

A. Lin, C. Li, Z. Xing, Q. Hu, K. Liang, L. Han, C. Wang, D. H. Hawke, S. Wang, Y. Zhang, Y. Wei, G. Ma, P. K. Park, J. Zhou, Y. Zhou, Z. Hu, Y. Zhou, J. R. Marks, H. Liang, M.-C. Hung, C. Lin, L. Yang, The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer. Nat. Cell Biol. 18, 213–224 (2016). [PubMed]