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Walsh L.,Stephens College | Gallagher W.M.,University College Dublin | Gallagher W.M.,OncoMark Ltd | Oconnor D.P.,Stephens College | Ni Chonghaile T.,Stephens College
Expert Review of Molecular Diagnostics | Year: 2016

Breast cancer is the most common cancer in women and great advancements have been made for individualised patient treatment. Through understanding the underlying altered biology in the different subtypes of breast cancer, targeted therapeutics have been developed. Unfortunately, resistance to targeted therapy, intrinsic or acquired, is a recurring theme in cancer treatment. Epigenetic-mediated resistance to targeted therapy has been identified across different types of cancer. In addition, tumorigenesis has also been linked to altered expression of epigenetic modifiers. Due to the reversible nature of epigenetic modifications, epigenetic proteins are appealing as therapeutic targets in both the primary and relapsed/resistant setting. In this review, we will discuss the current state of targetable epigenetic histone modifications and their diagnostic and therapeutic implications in breast cancer. © 2016 Taylor & Francis. Source

O'Hurley G.,Uppsala University | O'Hurley G.,University College Dublin | O'Hurley G.,OncoMark Ltd | Busch C.,Uppsala University | And 11 more authors.
PLoS ONE | Year: 2015

To better understand prostate function and disease, it is important to define and explore the molecular constituents that signify the prostate gland. The aim of this study was to define the prostate specific transcriptome and proteome, in comparison to 26 other human tissues. Deep sequencing of mRNA (RNA-seq) and immunohistochemistry-based protein profiling were combined to identify prostate specific gene expression patterns and to explore tissue biomarkers for potential clinical use in prostate cancer diagnostics. We identified 203 genes with elevated expression in the prostate, 22 of which showed more than five-fold higher expression levels compared to all other tissue types. In addition to previously well-known proteins we identified two poorly characterized proteins, TMEM79 and ACOXL, with potential to differentiate between benign and cancerous prostatic glands in tissue biopsies. In conclusion, we have applied a genome-wide analysis to identify the prostate specific proteome using transcriptomics and antibody-based protein profiling to identify genes with elevated expression in the prostate. Our data provides a starting point for further functional studies to explore the molecular repertoire of normal and diseased prostate including potential prostate cancer markers such as TMEM79 and ACOXL. © 2015 O'Hurley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source

Rexhepaj E.,Uppsala University | Agnarsdottir M.,Uppsala University | Bergman J.,Uppsala University | Edqvist P.-H.,Uppsala University | And 6 more authors.
PLoS ONE | Year: 2013

Aims:Immunohistochemistry is a routine practice in clinical cancer diagnostics and also an established technology for tissue-based research regarding biomarker discovery efforts. Tedious manual assessment of immunohistochemically stained tissue needs to be fully automated to take full advantage of the potential for high throughput analyses enabled by tissue microarrays and digital pathology. Such automated tools also need to be reproducible for different experimental conditions and biomarker targets. In this study we present a novel supervised melanoma specific pattern recognition approach that is fully automated and quantitative.Methods and Results:Melanoma samples were immunostained for the melanocyte specific target, Melan-A. Images representing immunostained melanoma tissue were then digitally processed to segment regions of interest, highlighting Melan-A positive and negative areas. Color deconvolution was applied to each region of interest to separate the channel containing the immunohistochemistry signal from the hematoxylin counterstaining channel. A support vector machine melanoma classification model was learned from a discovery melanoma patient cohort (n = 264) and subsequently validated on an independent cohort of melanoma patient tissue sample images (n = 157).Conclusion:Here we propose a novel method that takes advantage of utilizing an immuhistochemical marker highlighting melanocytes to fully automate the learning of a general melanoma cell classification model. The presented method can be applied on any protein of interest and thus provides a tool for quantification of immunohistochemistry-based protein expression in melanoma. © 2013 Rexhepaj et al. Source

Prencipe M.,University College Dublin | O'Neill A.,University College Dublin | O'Hurley G.,OncoMark Ltd | Nguyen L.K.,University College Dublin | And 7 more authors.
Prostate | Year: 2015

BACKGROUND Serum response factor (SRF) is an important transcription factor in castrate-resistant prostate cancer (CRPC). Since CRPC is associated with androgen receptor (AR) hypersensitivity, we investigated the relationship between SRF and AR. MATERIALS AND METHODS Transcriptional activity was assessed by luciferase assay. Cell proliferation was measured by MTT and flow cytometry. Protein expression in patients was assessed by immunohistochemistry. RESULTS To investigate AR involvement in SRF response to androgen, AR expression was down-regulated using siRNA. This resulted in the abrogation of SRF induction post-DHT. Moreover, DHT stimulation failed to induce SRF transcriptional activity in AR-negative PC346 DCC cells, which was only restored following AR over-expression. Next, SRF expression was down-regulated by siRNA, resulting in AR increased transcriptional activity in castrate-resistant LNCaP Abl cells but not in the parental LNCaP. This negative feedback loop in the resistant cells was confirmed by immunohistochemistry which showed a negative correlation between AR and SRF expression in CRPC bone metastases and a positive correlation in androgen-naïve prostatectomies. Cell proliferation was next assessed following SRF inhibition, demonstrating that SRF inhibition is more effective than AR inhibition in castrate-resistant cells. CONCLUSION Our data support SRF as a promising therapeutic target in combination with current treatments. © 2015 Wiley Periodicals, Inc. Source

Gremel G.,University College Dublin | Gremel G.,OncoMark Ltd | Ryan D.,University College Dublin | Rafferty M.,University College Dublin | And 15 more authors.
British Journal of Cancer | Year: 2011

Background: The homeobox containing transcription factor MSX2 is a key regulator of embryonic development and has been implicated to have a role in breast and pancreatic cancer. Methods: Using a selection of two-and three-dimensional in vitro assays and tissue microarrays (TMAs), the clinical and functional relevance of MSX2 in malignant melanoma was explored. A doxycyline-inducible over-expression system was applied to study the relevance of MSX2 in vitro. For TMA construction, tumour material from 218 melanoma patients was used. Results: Ectopic expression of MSX2 resulted in the induction of apoptosis and reduced the invasive capacity of melanoma cells in three-dimensional culture. MSX2 over-expression was shown to affect several signalling pathways associated with cell invasion and survival. Downregulation of N-Cadherin, induction of p21 and inhibition of both BCL2 and Survivin were observed. Cytoplasmic MSX2 expression was found to correlate significantly with increased recurrence-free survival (P=0.008). Nuclear expression of MSX2 did not result in significant survival correlations, suggesting that the beneficial effect of MSX2 may be independent of its DNA binding activity. Conclusions: MSX2 may be an important regulator of melanoma cell invasion and survival. Cytoplasmic expression of the protein was identified as biomarker for good prognosis in malignant melanoma patients. © 2011 Cancer Research UK. Source

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