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discipline of pathology research

The research groups in the Discipline of Pathology focus on the molecular mechanisms of breast cancer. We are studying the events that underpin breast cancer progression and heterogeneity through the evaluation of different stages of the disease from early precursor lesions through in situ tumours to invasive disease and metastasis. We are investigating a range of biomarkers, both individually and as panels, as potential prognostic and therapeutic targets in different breast cancer subtypes. Identification of biomarkers of complex molecular events will ultimately improve diagnosis of breast cancer and enable individualisation of treatments. Using the extensive archive of material provided by UCHG we apply immunohistochemistry and fluorescent in situ hybridisation (FISH) to formalin-fixed tumour samples for this and focus on large-scale validation of biomarkers using tissue microarrays.

 

Identification and validation of prognostic and predictive targets in breast cancer (GC)

Breast cancer is a heterogeneous disease. Patients with similar clinical and pathological features can respond differently to the same treatment and can have very different outcomes. We are investigating a range of novel biomarkers as potential prognostic and therapeutic  targets in breast cancer; and, in addition, we are investigating the molecular events that underpin breast cancer progression through the evaluation of different stages of the disease from early precursor lesions through in situ tumours to invasive disease and metastasis. We test molecular targets in paraffin embedded tumors and validate our findings in a large series of primary breast tumours for which we have detailed pathological and clinical data. We use immunohistochemical and in situ techniques and tissue microarray platforms. This work is done in close collaboration with the Department of Anatomic Pathology at University Hospital Galway. Identification of biomarkers of complex molecular events will ultimately improve diagnosis of breast cancer and further the individualisation of treatment for breast cancer.                                  

                                          
 

 

 

Unfolded protein response in cancer: regulation by microRNAs (SG)

The stressful conditions in the tumour microenvironment including low oxygen supply, nutrient deprivation and pH changes activate a range of cellular stress-response pathways. Tumour hypoxia is a common microenvironmental factor that adversely influences tumour phenotype and treatment response. Cellular adaptation to hypoxia occurs through multiple mechanisms, including activation of the unfolded protein response (UPR). UPR attempts to restore ER homeostasis by increasing ER bio-genesis, decreasing the influx of new proteins into the ER, promoting the transport of damaged proteins from the ER to the cytosol for degradation, and upregulating protein folding chaperones. Although the unfolded protein response is primarily a pro-survival response, in the event of prolonged or severe ER stress that is not resolved, the unfolded protein response switches to initiation of apoptosis. The molecular mechanisms involved in the transition of the UPR from a protective to an apoptotic phase are unclear.

 

microRNAs (miRNAs) have been shown to be critically involved in control of cell survival and cell death decisions. The main function of miRNAs is to direct posttranscriptional regulation of gene expression, typically by binding to 3’ UTR of cognate mRNAs and inhibiting their translation and/or stability. Global downregulation of miRNAs is a common feature of human tumours. Loss of miRNA biogenesis has been shown to enhance cancer progression. Further several components of miRNA biogenesis machinery (XPO5, DICER and TRBP) have been shown to act as haploinsufficient tumour suppressors. How the dysregulation of miRNA biogenesis promotes tumour development is not clearly understood. The main focus of research in my group is to evaluate the role of microRNAs in determining cell fate during conditions of ER stress.  We use a combination of molecular cell biology, transcriptomics, proteomics and miRNA expression profiling to address specific questions such as

·         What is the role of miRNAs in ER stress-induced apoptosis?

·         Does impaired miRNA biogenesis contribute to cancer progression by inhibiting ER stress-induced apoptosis?

 

 

DNA damage response and centrosome function in breast cancer (EB)

Breast cancer is categorised into several molecular subtypes; luminal subtypes characterised by over-expression of hormone receptors- oestrogen (ER) and progesterone (PR) and hormone negative subtypes including the HER2-positive subtype and the “basal-like” subtype. Unlike the luminal subtypes, the basal-like tumours are usually ER/PR-negative, and lack HER2 overexpression and as such are referred to as “triple-negative” breast cancers (TNBCs). Luminal type A, B and HER2-positive subtypes are currently treated with receptor-targeted strategies whereas TNBCs are notoriously difficult to treat with targeted therapies as they lack a receptor target and are currently managed using conventional non-specific chemotherapy. 

      Very little is known about the biological mechanisms that underlie the pathogenesis of the subtypes, in particular TNBCs, but profiling studies suggest that they may represent distinct biological entities. As genomic instability is a central event in tumourigenesis the findings that different levels and patterns of genomic instability exist in TNBCs, compared to other subtypes, suggests that different underlying pathogenic mechanisms may be active in each subtype. Genome integrity is maintained by DNA damage response (DDR) pathways and the extent to which the DDR is active in tumour cells is a measure of the level of genomic instability. A sound mitotic apparatus is also required to preserve chromosome integrity during cell division and centrosomal defects are associated with genetically unstable cells. My previous research has focused on the links between the DDR and centrosome function and role of centrosomal defects in promoting genomic instability (Dodson and Bourke et al., EMBO J 2004 , Bourke et al., EMBO Rep 2007, Saladino et al, Environ Mol Mutagen. 2009, Bourke et al Oncogene 2010, Brown et al., Oncogene 2010).  

      The focus of my research group is investigating if the DNA damage response and centrosome function are differentially regulated in triple negative compared with luminal subtypes of breast cancer. This will test the hypothesis that the ’intrinsic’ subtypes represent distinct biological entities possessing different hallmarks of genomic instability. The work employs breast cancer cell lines and patient tissue microarrays (TMAs) from the large biobank of breast cancers built here at UCHG. As an associate member of the Centre for Chromosome Biology (CCB) at NUIG, these projects include collaborations with Prof. Noels Lowndes and Prof. Ciaran Morrison of the CCB.

 

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