Dataset Information

The LINK-A lncRNA activates normoxic HIF1? signalling in triple-negative breast cancer.

ABSTRACT: Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1? phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1? stabilization, HIF1?-p300 interaction, and activation of HIF1? transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1? Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1? stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.

SUBMITTER: Lin A

PROVIDER: S-EPMC4791069 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.

Lin Aifu A Li Chunlai C Xing Zhen Z Hu Qingsong Q Liang Ke K Han Leng L Wang Cheng C Hawke David H DH Wang Shouyu S Zhang Yanyan Y Wei Yongkun Y Ma Guolin G Park Peter K PK Zhou Jianwei J Zhou Yan Y Hu Zhibin Z Zhou Yubin Y Marks Jeffery R JR Liang Han H Hung Mien-Chie MC Lin Chunru C Yang Liuqing L

Nature cell biology 20160111 2

Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, ...[more]

PMID: 26751287

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Project description:The so called "Triple Negative Breast Cancer" (TNBC) represents approximately 15-20% of breast cancers. This acronym simply means that the tumour does not express oestrogen receptor (ER) and progesterone receptor (PR) and does not exhibit amplification of the human epidermal growth factor receptor 2 (HER2) gene. Despite this unambiguous definition, TNBCs are an heterogeneous group of tumours with just one common clinical feature: a distinctly aggressive nature with higher rates of relapse and shorter overall survival in the metastatic setting compared with other subtypes of breast cancer. Because of the absence of well-defined molecular targets, cytotoxic chemotherapy is currently the only treatment option for TNBC. In the last decades, the use of more aggressive chemotherapy has produced a clear improvement of the prognosis in women with TNBC, but this approach results in an unacceptable deterioration in the quality of life, also if some support therapies try to relieve patients from distress. In addition, there is the general belief that it is impossible to further improve the prognosis of TNBC patients with chemotherapy alone. In view of that, there is a feverish search for new "clever drugs" able both to rescue chemo-resistant, and to reduce the burden of chemotherapy in chemo-responsive TNBC patients. A major obstacle to identifying actionable targets in TNBC is the vast disease heterogeneity both inter-tumour and intra-tumour and years of study have failed to demonstrate a single unifying alteration that is targetable in TNBC. TNBC is considered the subtype that best benefits from the neoadjuvant model, since the strong correlation between pathological Complete Response and long-term Disease-Free-Survival in these patients. In this review, we discuss the recent discoveries that have furthered our understanding of TNBC, with a focus on the subtyping of TNBC. We also explore the implications of these discoveries for future treatments and highlight the need for a completely different type of clinical trials.

Dataset Information

The LINK-A lncRNA activates normoxic HIF1? signalling in triple-negative breast cancer.

Publications

The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.

Similar Datasets

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