The role of long non-coding RNAs in breast cancer dissemination to the brain

Juan-Larrea, Naiara; Mather, Rebecca; Romero, Ignacio A.; Sibson, Nicola R. and Crea, Francesco (2018). The role of long non-coding RNAs in breast cancer dissemination to the brain. In: CRUK brain tumour conference, 1-3 May 2018, London.


Background. Metastatic breast cancer is an incurable disease, which carries a particularly poor prognosis when it occurs in the brain. Brain metastasis most commonly arises from ER-/PR-/Her2-(triple negative) malignancies. Long non-coding RNAs (lncRNAs) represent a vast and largely uncharted region of the human genome. Some lncRNAs play a key role in metastasis. Here we propose a novel approach to investigate the role of lncRNAs in breast cancer dissemination to the brain.
Methods. We have used bioinformatic predictions and analysis of clinical datasets to identify a shortlist of lncRNAs associated with the metastatic progression of triple negative breast cancers. Subsequently, the expression and function of selected lncRNAs is being determined in the triple negative breast cancer cell line MDA-MB-231 (which does not metastasize to the brain) and in the MDA-MB-231BR sub-line, which invariably invades the brain.
Results. Based on lnc2Cancer database, we have elaborated a shortlist of 15 lncRNAs associated with triple-negative and/or metastatic breast cancer progression. Analysis of a clinical dataset showed that higher expression of at least one of the selected transcripts (PCAT6) is associated with shorter metastasis-free survival in breast cancer patients (p<0.001, HR=1.55-3.01; log rank test on 1746 samples). We are currently measuring the expression of selected lncRNAs in MDA-MB-231BR vs MDA-MB-231 cells (qPCR). Transcripts up-regulated in the brain metastatic cell line will be ranked based on their fold-change. The most up-regulated lncRNA will then be selected for functional studies. As we have previously described, we will assess the effect of lncRNA silencing on MDA-MB-231BR cell proliferation, migration, invasion and adhesion to brain endothelial cells.
Conclusions. This study will pave the way for a better characterisation of the mechanisms leading to breast cancer cell dissemination to the brain.

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