Publications by authors named "Kyle B Matchett"

16 Publications

  • Page 1 of 1

A compound combination screening approach with potential to identify new treatment options for paediatric acute myeloid leukaemia.

Sci Rep 2020 10 28;10(1):18514. Epub 2020 Oct 28.

Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.

Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by genetics and morphology. The introduction of intensive chemotherapy treatments together with patient stratification and supportive therapy has resulted in a moderate improvement in patient prognosis. However, overall survival rates remain unacceptably poor, with only 65% of patients surviving longer than 5 years. Recently age-specific differences in AML have been identified, highlighting the need for tailored treatments for paediatric patients. Combination therapies have the potential to improve patient prognosis, while minimising harmful side-effects. In the laboratory setting, identifying key combinations from large drug libraries can be resource-intensive, prohibiting discovery and translation into the clinic. To minimise redundancy and maximise discovery, we undertook a multiplex screen of 80 apoptotic-inducing agents in paediatric AML pre-clinical models. The screen was designed using an all-pairs testing algorithm, which ensured that all pairs of compounds could be tested, while minimising the number of wells used. We identified a combination of ABT-737, a Bcl-2 family inhibitor and Purvalanol A, a CDK inhibitor, as a potential targeted therapy for AML patients with an MLL rearrangement and an FLT3-ITD. Our approach has the potential to reduce resource-intensity and time associated with the identification of novel combination therapies.
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http://dx.doi.org/10.1038/s41598-020-75453-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595190PMC
October 2020

Tibetan , an allele with loss-of-function properties.

Proc Natl Acad Sci U S A 2020 06 15;117(22):12230-12238. Epub 2020 May 15.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;

Tibetans have adapted to the chronic hypoxia of high altitude and display a distinctive suite of physiologic adaptations, including augmented hypoxic ventilatory response and resistance to pulmonary hypertension. Genome-wide studies have consistently identified compelling genetic signatures of natural selection in two genes of the Hypoxia Inducible Factor pathway, and The product of the former induces the degradation of the product of the latter. Key issues regarding Tibetan are whether it is a gain-of-function or loss-of-function allele, and how it might contribute to high-altitude adaptation. Tibetan PHD2 possesses two amino acid changes, D4E and C127S. We previously showed that in vitro, Tibetan PHD2 is defective in its interaction with p23, a cochaperone of the HSP90 pathway, and we proposed that Tibetan is a loss-of-function allele. Here, we report that additional PHD2 mutations at or near Asp-4 or Cys-127 impair interaction with p23 in vitro. We find that mice with the Tibetan allele display augmented hypoxic ventilatory response, supporting this loss-of-function proposal. This is phenocopied by mice with a mutation in that abrogates the PHD2:p23 interaction. haploinsufficiency, but not the Tibetan allele, ameliorates hypoxia-induced increases in right ventricular systolic pressure. The Tibetan allele is not associated with hemoglobin levels in mice. We propose that Tibetans possess genetic alterations that both activate and inhibit selective outputs of the HIF pathway to facilitate successful adaptation to the chronic hypoxia of high altitude.
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http://dx.doi.org/10.1073/pnas.1920546117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275716PMC
June 2020

Novel Ran-RCC1 Inhibitory Peptide-Loaded Nanoparticles Have Anti-Cancer Efficacy In Vitro and In Vivo.

Cancers (Basel) 2019 Feb 14;11(2). Epub 2019 Feb 14.

Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK.

The delivery of anticancer agents to their subcellular sites of action is a significant challenge for effective cancer therapy. Peptides, which are integral to several oncogenic pathways, have significant potential to be utilised as cancer therapeutics due to their selectivity, high potency and lack of normal cell toxicity. Novel Ras protein-Regulator of chromosome condensation 1 (Ran-RCC1) inhibitory peptides designed to interact with Ran, a novel therapeutic target in breast cancer, were delivered by entrapment into polyethylene glycol-poly (lactic-co-glycolic acid) PEG-PLGA polymeric nanoparticles (NPs). A modified double emulsion solvent evaporation technique was used to optimise the physicochemical properties of these peptide-loaded biodegradable NPs. The anti-cancer activity of peptide-loaded NPs was studied in vitro using Ran-expressing metastatic breast (MDA-MB-231) and lung cancer (A549) cell lines, and in vivo using Solid Ehrlich Carcinoma-bearing mice. The anti-metastatic activity of peptide-loaded NPs was investigated using migration, invasion and colony formation assays in vitro. A PEG-PLGA-nanoparticle encapsulating -terminal peptide showed a pronounced antitumor and anti-metastatic action in lung and breast cancer cells in vitro and caused a significant reduction of tumor volume and associated tumor growth inhibition of breast cancer model in vivo. These findings suggest that the novel inhibitory peptides encapsulated into PEGylated PLGA NPs are delivered effectively to interact and deactivate Ran. This novel Ran-targeting peptide construct shows significant potential for therapy of breast cancer and other cancers mediated by Ran overexpression.
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http://dx.doi.org/10.3390/cancers11020222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406988PMC
February 2019

Intradermal Delivery of a Near-Infrared Photosensitizer Using Dissolving Microneedle Arrays.

J Pharm Sci 2018 09 1;107(9):2439-2450. Epub 2018 Jun 1.

Queen's University Belfast, School of Pharmacy, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK. Electronic address:

Nodular basal cell carcinoma is a deep skin lesion and one of the most common cancers. Conventional photodynamic therapy is limited to treatment of superficial skin lesions. The parenteral administration of near-IR preformed photosensitizers suffers from poor selectivity and may result in prolonged skin photosensitivity. Microneedles (MNs) can provide localized drug delivery to skin lesions. Intradermal delivery of the preformed near-IR photosensitizer; 5,10,15,20-tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl bacteriochlorin (Redaporfin™) using dissolving MN was successful in vitro and in vivo. MN demonstrated complete dissolution 30 min after skin application and showed sufficient mechanical strength to penetrate the skin to a depth of 450 μm. In vitro deposition studies illustrated that the drug was delivered and detected down to 5 mm in skin. In vivo biodistribution studies in athymic nude mice Crl:NU(NCr)-Foxn1 showed both fast initial release and localized drug delivery. The MN-treated mice showed a progressive decrease in the fluorescence intensity at the application site over the 7-day experiment period, with the highest and lowest fluorescence intensities measured being 9.2 × 10 ± 2.5 × 10 and 3.8 × 10 ± 1.6 × 10 p/s, respectively. By day 7, there was some migration of fluorescence away from the site of initial MN application. However, the majority of the body surfaces showed fluorescence levels that were comparable to those seen in the negative control group. This work suggests utility for polymeric MN arrays in minimally invasive intradermal delivery to enhance photodynamic therapy of deep skin lesions.
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http://dx.doi.org/10.1016/j.xphs.2018.05.017DOI Listing
September 2018

Advances in Precision Medicine: Tailoring Individualized Therapies.

Cancers (Basel) 2017 Oct 25;9(11). Epub 2017 Oct 25.

Discipline of Surgery, School of Medicine, The Lambe Institute for Translational Research, National University of Ireland Galway, Galway H91 YR71, Ireland.

The traditional bench-to-bedside pipeline involves using model systems and patient samples to provide insights into pathways deregulated in cancer. This discovery reveals new biomarkers and therapeutic targets, ultimately stratifying patients and informing cohort-based treatment options. Precision medicine (molecular profiling of individual tumors combined with established clinical-pathological parameters) reveals, in real-time, individual patient's diagnostic and prognostic risk profile, informing tailored and tumor-specific treatment plans. Here we discuss advances in precision medicine presented at the Irish Association for Cancer Research Annual Meeting, highlighting examples where personalized medicine approaches have led to precision discovery in individual tumors, informing customized treatment programs.
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http://dx.doi.org/10.3390/cancers9110146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704164PMC
October 2017

Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy.

Oncotarget 2017 Sep 1;8(40):67891-67903. Epub 2017 Jul 1.

Blood Cancer Research Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.

Several histone deacetylase inhibitors including Vorinostat have received FDA approval for the treatment of haematological malignancies. However, data from these trials indicate that Vorinostat has limited efficacy as a monotherapy, prompting the need for rational design of combination therapies. A number of epi-sensitised pathways, including sonic hedgehog (SHH), were identified in AML cells by integration of global patterns of histone H3 lysine 9 (H3K9) acetylation with transcriptomic analysis following Vorinostat-treatment. Direct targeting of the SHH pathway with SANT-1, following Vorinostat induced epi-sensitisation, resulted in synergistic cell death of AML cells. In addition, xenograft studies demonstrated that combination therapy induced a marked reduction in leukemic burden compared to control or single agents. Together, the data supports epi-sensitisation as a potential component of the strategy for the rational development of combination therapies in AML.
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http://dx.doi.org/10.18632/oncotarget.18910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620222PMC
September 2017

Erythropoietin drives breast cancer progression by activation of its receptor EPOR.

Oncotarget 2017 Jun;8(24):38251-38263

Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7AE, UK.

Breast cancer is a leading cause of cancer-related deaths. Anemia is common in breast cancer patients and can be treated with blood transfusions or with recombinant erythropoietin (EPO) to stimulate red blood cell production. Clinical studies have indicated decreased survival in some groups of cancer patients treated with EPO. Numerous tumor cells express the EPO receptor (EPOR), posing a risk that EPO treatment would enhance tumor growth, but the mechanisms involved in breast tumor progression are poorly understood.Here, we have examined the functional role of the EPO-EPOR axis in pre-clinical models of breast cancer. EPO induced the activation of PI3K/AKT and MAPK pathways in human breast cancer cell lines. EPOR knockdown abrogated human tumor cell growth, induced apoptosis through Bim, reduced invasiveness, and caused downregulation of MYC expression. EPO-induced MYC expression is mediated through the PI3K/AKT and MAPK pathways, and overexpression of MYC partially rescued loss of cell proliferation caused by EPOR downregulation. In a xenotransplantation model, designed to simulate recombinant EPO therapy in breast cancer patients, knockdown of EPOR markedly reduced tumor growth.Thus, our experiments in vitro and in vivo demonstrate that functional EPOR signaling is essential for the tumor-promoting effects of EPO and underline the importance of the EPO-EPOR axis in breast tumor progression.
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http://dx.doi.org/10.18632/oncotarget.16368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503530PMC
June 2017

Nano-encapsulation of a novel anti-Ran-GTPase peptide for blockade of regulator of chromosome condensation 1 (RCC1) function in MDA-MB-231 breast cancer cells.

Int J Pharm 2017 04 2;521(1-2):40-53. Epub 2017 Feb 2.

School of Pharmacy and Pharmaceutical Sciences, Saad Centre for Pharmacy and Diabetes, Ulster University, Cromore Road, Coleraine, Co. Londonderry, BT52 1SA, UK. Electronic address:

Ran is a small ras-related GTPase and is highly expressed in aggressive breast carcinoma. Overexpression induces malignant transformation and drives metastatic growth. We have designed a novel series of anti-Ran-GTPase peptides, which prevents Ran hydrolysis and activation, and although they display effectiveness in silico, peptide activity is suboptimal in vitro due to reduced bioavailability and poor delivery. To overcome this drawback, we delivered an anti-Ran-GTPase peptide using encapsulation in PLGA-based nanoparticles (NP). Formulation variables within a double emulsion solvent evaporation technique were controlled to optimise physicochemical properties. NP were spherical and negatively charged with a mean diameter of 182-277nm. Peptide integrity and stability were maintained after encapsulation and release kinetics followed a sustained profile. We were interested in the relationship between cellular uptake and poly(ethylene glycol) (PEG) in the NP matrix, with results showing enhanced in vitro uptake with increasing PEG content. Peptide-loaded, pegylated (10% PEG)-PLGA NP induced significant cytotoxic and apoptotic effects in MDA-MB-231 breast cancer cells, with no evidence of similar effects in cells pulsed with free peptide. Western blot analysis showed that encapsulated peptide interfered with the proposed signal transduction pathway of the Ran gene. Our novel blockade peptide prevented Ran activation by blockage of regulator of chromosome condensation 1 (RCC1) following peptide release directly in the cytoplasm once endocytosis of the peptide-loaded nanoparticle has occurred. RCC1 blockage was effective only when a nanoparticulate delivery approach was adopted.
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http://dx.doi.org/10.1016/j.ijpharm.2017.02.006DOI Listing
April 2017

Big Data-Led Cancer Research, Application, and Insights.

Cancer Res 2016 11 20;76(21):6167-6170. Epub 2016 Oct 20.

Graduate Entry Medical School, University of Limerick, Limerick, Ireland.

Insights distilled from integrating multiple big-data or "omic" datasets have revealed functional hierarchies of molecular networks driving tumorigenesis and modifiers of treatment response. Identifying these novel key regulatory and dysregulated elements is now informing personalized medicine. Crucially, although there are many advantages to this approach, there are several key considerations to address. Here, we examine how this big data-led approach is impacting many diverse areas of cancer research, through review of the key presentations given at the Irish Association for Cancer Research Meeting and importantly how the results may be applied to positively affect patient outcomes. Cancer Res; 76(21); 6167-70. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0860DOI Listing
November 2016

Ran GTPase promotes cancer progression via Met recepto-rmediated downstream signaling.

Oncotarget 2016 11;7(46):75854-75864

Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire, UK.

It has been shown previously that cancer cells with an activated oncogenic pathway, including Met activation, require Ran for growth and survival.Here, we show that knockdown of Ran leads to a reduction of Met receptor expression in several breast and lung cancer cell lines. This, in turn suppressed HGF expression and the Met-mediated activation of the Akt pathway, as well as cell adhesion, migration, and invasion. In a cell line model where Met amplification has previously been shown to contribute to gefitinib resistance, Ran knockdown sensitized cells to gefitinib-mediated inhibition of Akt and ERK1/2 phosphorylation and consequently reduced cell proliferation. We further demonstrate that Met reduction-mediated by knockdown of Ran, occurs at the post-transcriptional level, probably via a matrix metalloproteinase. Moreover, the level of immunoreactive Ran and Met are positively associated in human breast cancer specimens, suggesting that a high level of Ran may be a pre-requisite for Met overexpression. Interestingly, a high level of immunoreactive Ran dictates the prognostic significance of Met, indicating that the co-overexpression of Met and Ran may be associated with cancer progression and could be used in combination as a prognostic indicator.
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http://dx.doi.org/10.18632/oncotarget.12420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342783PMC
November 2016

Low-dose salinomycin induces anti-leukemic responses in AML and MLL.

Oncotarget 2016 Nov;7(45):73448-73461

Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.

Development of anti-cancer drugs towards clinical application is costly and inefficient. Large screens of drugs, efficacious for non-cancer disease, are currently being used to identify candidates for repurposing based on their anti-cancer properties. Here, we show that low-dose salinomycin, a coccidiostat ionophore previously identified in a breast cancer screen, has anti-leukemic efficacy. AML and MLLr cell lines, primary cells and patient samples were sensitive to submicromolar salinomycin. Most strikingly, colony formation of normal hematopoietic cells was unaffected by salinomycin, demonstrating a lack of hemotoxicity at the effective concentrations. Furthermore, salinomycin treatment of primary cells resulted in loss of leukemia repopulation ability following transplantation, as demonstrated by extended recipient survival compared to controls. Bioinformatic analysis of a 17-gene signature identified and validated in primary MLLr cells, uncovered immunomodulatory pathways, hubs and protein interactions as potential transducers of low dose salinomycin treatment. Additionally, increased protein expression of p62/Sqstm1, encoded for by one of the 17 signature genes, demonstrates a role for salinomycin in aggresome/vesicle formation indicative of an autophagic response.Together, the data support the efficacy of salinomycin as an anti-leukemic at non-hemotoxic concentrations. Further investigation alone or in combination with other therapies is warranted for future clinical trial.
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http://dx.doi.org/10.18632/oncotarget.11866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341990PMC
November 2016

Protein deregulation associated with breast cancer metastasis.

Cytokine Growth Factor Rev 2015 Aug 31;26(4):415-23. Epub 2015 May 31.

Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire BD7 1DP, United Kingdom. Electronic address:

Breast cancer is one of the most prevalent malignancies worldwide. It consists of a group of tumor cells that have the ability to grow uncontrollably, overcome replicative senescence (tumor progression) and metastasize within the body. Metastases are processes that consist of an array of complex gene dysregulation events. Although these processes are still not fully understood, the dysregulation of a number of key proteins must take place if the tumor cells are to disseminate and metastasize. It is now widely accepted that future effective and innovative treatments of cancer metastasis will have to encompass all the major components of malignant transformation. For this reason, much research is now being carried out into the mechanisms that govern the malignant transformation processes. Recent research has identified key genes involved in the development of metastases, as well as their mechanisms of action. A detailed understanding of the encoded proteins and their interrelationship generates the possibility of developing novel therapeutic approaches. This review will focus on a select group of proteins, often deregulated in breast cancer metastasis, which have shown therapeutic promise, notably, EMT, E-cadherin, Osteopontin, PEA3, Transforming Growth Factor Beta (TGF-β) and Ran.
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http://dx.doi.org/10.1016/j.cytogfr.2015.05.002DOI Listing
August 2015

Novel antibodies directed against the human erythropoietin receptor: creating a basis for clinical implementation.

Br J Haematol 2015 Feb 4;168(3):429-42. Epub 2014 Oct 4.

Northern Ireland Molecular Pathology Laboratory, Belfast Health & Social Care Trust, Queen's University Belfast, Belfast, UK; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.

Recombinant human erythropoietin (rHuEPO) is an effective treatment for anaemia but concerns that it causes disease progression in cancer patients by activation of EPO receptors (EPOR) in tumour tissue have been controversial and have restricted its clinical use. Initial clinical studies were flawed because they used polyclonal antibodies, later shown to lack specificity for EPOR. Moreover, multiple isoforms of EPOR caused by differential splicing have been reported in cancer cell lines at the mRNA level but investigations of these variants and their potential impact on tumour progression, have been hampered by lack of suitable antibodies. The EpoCan consortium seeks to promote improved pathological testing of EPOR, leading to safer clinical use of rHuEPO, by producing well characterized EPOR antibodies. Using novel genetic and traditional peptide immunization protocols, we have produced mouse and rat monoclonal antibodies, and show that several of these specifically recognize EPOR by Western blot, immunoprecipitation, immunofluorescence, flow cytometry and immunohistochemistry in cell lines and clinical material. Widespread availability of these antibodies should enable the research community to gain a better understanding of the role of EPOR in cancer, and eventually to distinguish patients who can be treated safely by rHuEPO from those at increased risk from treatment.
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http://dx.doi.org/10.1111/bjh.13133DOI Listing
February 2015

BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability.

Cancer Res 2014 May 17;74(10):2773-2784. Epub 2014 Mar 17.

Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.

Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptor-α-negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-2611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024319PMC
May 2014

Ran GTPase in nuclear envelope formation and cancer metastasis.

Adv Exp Med Biol 2014 ;773:323-51

Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL, UK,

Ran is a small ras-related GTPase that controls the nucleocytoplasmic exchange of macromolecules across the nuclear envelope. It binds to chromatin early during nuclear formation and has important roles during the eukaryotic cell cycle, where it regulates mitotic spindle assembly, nuclear envelope formation and cell cycle checkpoint control. Like other GTPases, Ran relies on the cycling between GTP-bound and GDP-bound conformations to interact with effector proteins and regulate these processes. In nucleocytoplasmic transport, Ran shuttles across the nuclear envelope through nuclear pores. It is concentrated in the nucleus by an active import mechanism where it generates a high concentration of RanGTP by nucleotide exchange. It controls the assembly and disassembly of a range of complexes that are formed between Ran-binding proteins and cellular cargo to maintain rapid nuclear transport. Ran also has been identified as an essential protein in nuclear envelope formation in eukaryotes. This mechanism is dependent on importin-β, which regulates the assembly of further complexes important in this process, such as Nup107-Nup160. A strong body of evidence is emerging implicating Ran as a key protein in the metastatic progression of cancer. Ran is overexpressed in a range of tumors, such as breast and renal, and these perturbed levels are associated with local invasion, metastasis and reduced patient survival. Furthermore, tumors with oncogenic KRAS or PIK3CA mutations are addicted to Ran expression, which yields exciting future therapeutic opportunities.
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http://dx.doi.org/10.1007/978-1-4899-8032-8_15DOI Listing
September 2014

Molecular and clinicopathological markers of prognosis in breast cancer.

Expert Rev Mol Diagn 2013 Jun;13(5):481-98

Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.

A vast body of research in breast cancer prognostication has accumulated. Yet despite this, patients within current prognostic categories may have significantly different outcomes. There is a need to more accurately divide those cancer types associated with an excellent prognosis from those requiring more aggressive therapy. Gene expression array studies have revealed the numerous molecular breast cancer subtypes that are associated with differing outcomes. Furthermore, as next generation technologies evolve and further reveal the complexities of breast cancer, it is likely that existing prognostic approaches will become progressively refined. Future prognostication in breast cancer requires a morphomolecular, multifaceted approach involving the assessment of anatomical disease extent and levels of protein, DNA and RNA expression. One of the major challenges in prognostication will be the integration of potential assays into existing clinical systems and identification of appropriate patient subgroups for analysis.
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http://dx.doi.org/10.1586/erm.13.29DOI Listing
June 2013
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