Biology subjects

Harris, A. L.

Publications and source records attributed to Harris, A. L..

4 recordsLinked to original sources

bioRxiv2018

Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine-resistance in breast cancer

Tumor hypoxia is associated with poor patient outcomes in estrogen receptor- (ER) positive breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer and it is regulated by HIF1 both in-vitro and in-vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ER but it became predominantly a HIF-1-dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1 and ER overlap in SNAT2s cis-regulatory elements. In addition, the downregulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia.\n\nOverexpression of SNAT2 in-vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ER inhibition, in hypoxia, or when glutamine levels were low. SNAT2 upregulation in-vivo caused complete resistance to anti-estrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlate with HIF-1 and worse outcome in patients given anti-estrogen therapy. Our findings show a switch in regulation of SNAT2 between ER and HIF-1, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer.

cancer biology↗

bioRxiv2018

Endogenous miRNA sponges mediate the generation of oscillatory dynamics for a non-coding RNA network

Oscillations are crucial to the sustenance of living organisms, across a wide variety of biological processes. In eukaryotes, oscillatory dynamics are thought to arise from interactions at the protein and RNA levels; however, the role of non-coding RNA in regulating these dynamics remains understudied. In this work, using a mathematical model, we show how non-coding RNA acting as microRNA (miRNA) sponges in a conserved miRNA - transcription factor feedback motif, can give rise to oscillatory behaviour. Control of these non-coding RNA can dynamically create oscillations or stability, and we show how this behaviour predisposes to oscillations in the stochastic limit. These results, supported by emerging evidence for the role of miRNA sponges in development, point towards key roles of different species of miRNA sponges, such as circular RNA, potentially in the maintenance of yet unexplained oscillatory behaviour. These results help to provide a paradigm for understanding functional differences between the many redundant, but distinct RNA species thought to act as miRNA sponges in nature, such as long non-coding RNA, pseudogenes, competing mRNA, circular RNA, and 3 UTRs.\n\nAuthor summaryWe analyze the effects of a newly discovered species of non-coding RNA, acting as microRNA (miRNA) sponges, on intracellular signalling dynamics. We show that oscillatory behaviour can arise in a time-varying manner in an over-represented transcriptional feedback network. These results point towards novel hypotheses for the roles of different species of miRNA sponges, such as their increasingly understood role in neural development.

systems biology↗

bioRxiv2017

Pan-cancer characterisation of microRNA with hallmarks of cancer reveals role of microRNA-mediated downregulation of tumour suppressor genes

microRNA are key regulators of the human transcriptome across a number of diverse biological processes, such as development, aging, and cancer, where particular miRNA have been identified as tumour suppressive and oncogenic. In this work, we sought to elucidate, in a comprehensive manner, across 15 epithelial cancer types comprising 7,316 clinical samples from the Cancer Genome Atlas, the association of miRNA expression and target regulation with the pheno-typic hallmarks of cancer. Utilising penalized regression techniques to integrate transcriptomic, methylation and mutation data, we find evidence for a complex map of interactions underlying the relationship of miRNA regulation and the hallmarks of cancer. This highlighted high redundancy for the oncomiR-1 cluster of oncogenic miRNAs, in particular hsa-miR-17-5p. In addition, we reveal extensive miRNA regulation of tumour suppressor genes such as PTEN, FAT4, and CDK12, uncovering an alternative mechanism of repression in the absence of mutation, methylation or copy number changes.

genomics↗

bioRxiv2017

sigQC: A procedural approach for standardising the evaluation of gene signatures

With the increase in next generation sequencing generating large amounts of genomic data, gene expression signatures are becoming critically important tools, poised to make a large impact on the diagnosis, management and prognosis for a number of diseases. Increasingly, it is becoming necessary to determine whether a gene expression signature may apply to a dataset, but no standard quality control methodology exists. In this work, we introduce the first protocol, implemented in an R package sigQC, enabling a streamlined methodological and standardised approach for the quality control validation of gene signatures on independent data sets. The emphasis in this work is in showing the critical quality control steps involved in the generation of a clinically and biologically useful, transportable gene signature, including ensuring sufficient expression, variability, and autocorrelation of a signature. We demonstrate the application of the protocol in this work, showing how the outputs created from sigQC may be used for the evaluation of gene signatures on large-scale gene expression data in cancer.

bioinformatics↗