Signaling Pathway Could Be Target of New Triple Negative Breast Cancer Treatment

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Dr. Chunru Lin PhD
Assistant Professor, Department of Molecular and Cellular Oncology,
Division of Basic Science Research and
Graduate School of Biomedical Sciences
The University of Texas MD Anderson Cancer Center, Houston, TX

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Lin: Triple-Negative Breast Cancer (TNBC) continues to be a serious healthcare problem despite improvements in early detection and treatment; lncRNAs are one of the emerging elements that make the process of understanding breast cancer development and progression so complex yet thorough. Thus, it is imperative to include an examination of lncRNAs when studying breast cancer, especially when researching challenging questions related to relapses and recurrences of breast cancer that occur after targeted therapeutic treatments. A perspective that incorporates lncRNAs into the discussion of breast cancer biology could be the conceptual advance that is necessary to encourage further breakthroughs.

Our research reveals the biological functional roles of cytoplasmic lncRNAs as signaling pathway mediators and catalysts that serve as indispensable components of signal transduction cascades and gene networks. This understanding could transform the prevailing dogma of the field of signal transduction. This study has identified a previously unknown mechanism for HIF stabilization and signal transduction, which is triggered by the HB-EGF bound EGFR/GPNMB heterodimer and is mediated by LINK-A-dependent recruitment of two kinases, BRK and LRRK2, to phosphorylate HIF1α at two new sites, leading to HIF1α stabilization and interaction with p300 for transcriptional activation; this further results in cancer glycolytic reprogramming under normoxic conditions. LINK-A is the first demonstrated lncRNA that acts as a key mediator of biological signaling pathways, which suggests the potential for the involvement of other lncRNAs as mediators of numerous signaling pathways.

Importantly, expression of LINK-A and activation of the LINK-A mediated signaling pathway are both correlated with TNBC. Targeting LINK-A with LNAs (Locked Nucleic Acids) serves as an encouraging strategy to block reprogramming of glucose metabolism in TNBC with therapeutic potential. 

MedicalResearch: What should clinicians and patients take away from your report?

Dr. Lin: Firstly, our report has identified the prognostic value of the lncRNA LINK-A for TNBC. Analysis of the expression status of LINK-A in the TCGA database and RNAscope of a fresh frozen breast cancer tissue microarray have indicated that LINK-A is significantly upregulated in  Triple-Negative Breast Cancer patient tissues in comparison to other subtypes of breast cancer. Importantly, we have examined the expression level of LINK-A in fresh frozen breast cancer tissues and have found that high levels of LINK-A expression are significantly correlated with worse RFS (recurrence free survival) in breast cancer patients. Therefore, the lncRNA LINK-A may serve as a biomarker for further classification of TNBC.

In addition, our report identified four novel phosphorylation sites of GPNMB, BRK, and HIF1α, which are critical for glycolytic reprogramming in Triple-Negative Breast Cancer. We have pinpointed novel phosphorylation sites of GPNMB (Y525), BRK (Y351), and HIF1α (Y565 and T797), which are highly phosphorylated and are correlated with LINK-A expression in TNBC tissue samples. The statuses of these phosphorylation sites are negatively correlated with the outcome of TNBC patients, which suggests that the newly identified signaling pathway from our research plays a crucial role in TNBC and may provide wide-ranging therapeutic targets for patients with TNBC. 

MedicalResearch: What recommendations do you have for future research as a result of this study? 

Dr. Lin: Our findings, with relevance to both pathological and homeostatic conditions of LINK-A, should have broad impact on the fields of lncRNA and signal transduction research and garner interest in a new field of study that focuses on lncRNA involvement in signal transduction networks.

Clinically, given that LINK-A is required for the activation of HIF signaling, LINK-A could be a promising novel therapeutic target to synergize with EGFR triggered HIF signaling inhibitors in breast cancer treatment. Future work can be done to test whether the inactivation of LINK-A individually with antisense nucleic acids, or in conjunction with drugs of specific mono-antibodies that target the identified signaling pathways will render breast cancer cells more susceptible to EGFR, GPNMB, or HIF inhibitors, such as Cetuximab or Panitumumab, mediate cell growth suppression in vitro, and tumor shrinkage in vivo, which would be of benefit to people seeking to understand the pharmacology of cancer therapies using in vitro and in vivo technologies.


Aifu Lin, Chunlai Li, Zhen Xing, Qingsong Hu, Ke Liang, Leng Han, Cheng Wang, David H. Hawke, Shouyu Wang, Yanyan Zhang, Yongkun Wei, Guolin Ma, Peter K. Park, Jianwei Zhou, Yan Zhou, Zhibin Hu, Yubin Zhou, Jeffery R. Marks, Han Liang, Mien-Chie Hung, Chunru Lin, Liuqing Yang. The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer. Nature Cell Biology, 2016; DOI:10.1038/ncb3295

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Dr. Chunru Lin PhD (2016). Signaling Pathway Could Be Target of New Triple Negative Breast Cancer Treatment 

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Last Updated on January 13, 2016 by Marie Benz MD FAAD