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Identification, roles and mechanisms of long non-coding RNAs in stem cells and metastasis in breast cancer.

Paul Cathcart

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Funding source

Medical Research Council (MRC)
Aims: Dysregulation of lncRNAs have been implicated in many human cancers, however no significant findings have thus far emerged in the cancer stem cell field. Breast cancer stem cell populations capable of self-renewal and tumorigenesis are linked to the most malignant features of the disease. We propose to disentangle the roles of lncRNAs in the genetic circuitry of different breast cancers to facilitate targeted therapeutics of the future. Objectives: i) To identify lncRNAs differentially expressed in BCSCs, ii) To investigate the binding and transcriptional effects of known BCSC transcription factors on the lncRNA transcriptional landscape they produce, iii) To use loss- and gain-of-function experiments to determine the contribution of selected lncRNAs to the BCSC phenotype, iv) To investigate mechanisms of lncRNA regulation, focusing on subcellular localisation, association with specific genomic sites, and presence of binding motifs with predictable functions. Further, using Ago2 immunoprecipitation followed by RNA-seq, we will evaluate the binding of Ago2-miRNA complexes to the lncRNAs indicative of miRNA sponge function, v) To understand their clinical relevance and establish their role as biomarkers. Methodology: This project uses a range of cell and molecular biology techniques, bioinformatics and tissue handling techniques, which are well established in the host laboratory. Scientific and Medical Opportunities: Over the past five years, research in the host laboratory has focused primarily on the role of non-coding RNAs in cancer and their potential as biomarkers and therapeutic targets. The lab has published extensively on the relationship(s) between miRNAs and the estrogen receptor-alpha following their discovery of a novel regulatory feedback loop involving miRNAs and the ER-alpha. Ongoing work aims to demonstrate that transcriptional regulation is a general mechanism of miRNA biogenesis with relevance to breast cancer.

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