Publications
108 results found
Fletcher CE, Dart DA, Bevan CL, 2014, Interplay between steroid signalling and microRNAs: implications for hormone-dependent cancers, Endocrine-Related Cancer, Vol: 21, Pages: R409-R429, ISSN: 1479-6821
Hormones are key drivers of cancer development. To date, interest has largely been focussed on the classical model of hormonal gene regulation, but there is increasing evidence for a role of hormone signalling pathways in post-translational regulation of gene expression. In particular, a complex and dynamic network of bi-directional interactions with microRNAs (miRs) at all stages of biogenesis and during target gene repression is emerging. miRs, which act mainly by negatively regulating gene expression through association with 3′-UTRs of mRNA species, are increasingly understood to be important in development, normal physiology and pathogenesis. Given recent demonstrations of altered miR profiles in a diverse range of cancers, their ability to function as oncogenes or tumour suppressors, and hormonal regulation of miRs, understanding mechanisms by which miRs are generated and regulated is vitally important. miRs are transcribed by RNA polymerase II and then processed in the nucleus by the Drosha-containing Microprocessor complex and in the cytoplasm by Dicer, before mature miRs are incorporated into the RNA-induced silencing complex. It is increasingly evident that multiple cellular signalling pathways converge upon the miR biogenesis cascade, adding further layers of regulatory complexity to modulate miR maturation. This review summarises recent advances in identification of novel components and regulators of the Microprocessor and Dicer complexes, with particular emphasis on the role of hormone signalling pathways in regulating their activity. Understanding hormone regulation of miR production and how this is perturbed in cancer are critical for the development of miR-based therapeutics and biomarkers.
Fioretti FM, Sita-Lumsden A, Bevan CL, et al., 2014, Revising the role of the androgen receptor in breast cancer, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 52, Pages: R257-R265, ISSN: 0952-5041
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- Citations: 60
Brooke GN, Powell SM, Lavery DN, et al., 2014, Engineered repressors are potent inhibitors of androgen receptor activity, Oncotarget, Vol: 5, Pages: 959-969, ISSN: 1949-2553
Prostate cancer growth is dependent upon the Androgen Receptor (AR) pathway, hence therapies for this disease often target this signalling axis. Such therapies are successful in the majority of patients but invariably fail after a median of 2 years and tumours progress to a castrate resistant stage (CRPC). Much evidence exists to suggest that the AR remains key to CRPC growth and hence remains a valid therapeutic target. Here we describe a novel method to inhibit AR activity, consisting of an interaction motif, that binds to the AR ligand-binding domain, fused to repression domains. These ‘engineered repressors’ are potent inhibitors of AR activity and prostate cancer cell growth and importantly inhibit the AR under circumstances in which conventional therapies would be predicted to fail, such as AR mutation and altered cofactor levels.
Sita-Lumsden A, Fletcher CE, Dart DA, et al., 2013, Circulating nucleic acids as biomarkers of prostate cancer, BIOMARKERS IN MEDICINE, Vol: 7, Pages: 867-877, ISSN: 1752-0363
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- Citations: 19
Dart DA, Waxman J, Aboagye EO, et al., 2013, Visualising Androgen Receptor Activity in Male and Female Mice, PLOS One, Vol: 8, ISSN: 1932-6203
Androgens, required for normal development and fertility of males and females, have vital roles in the reproductivetract, brain, cardiovascular system, smooth muscle and bone. Androgens function via the androgen receptor (AR), aligand-dependent transcription factor. To assay and localise AR activity in vivo we generated the transgenic “ARELuc”mouse, expressing a luciferase reporter gene under the control of activated endogenous AR. In vivo imaging ofandrogen-mediated luciferase activity revealed several strongly expressing tissues in the male mouse as expectedand also in certain female tissues. In males the testes, prostate, seminal vesicles and bone marrow all showed highAR activity. In females, strong activity was seen in the ovaries, uterus, omentum tissue and mammary glands. In bothsexes AR expression and activity was also found in salivary glands, the eye (and associated glands), adipose tissue,spleen and, notably, regions of the brain. Luciferase protein expression was found in the same cell layers asandrogen receptor expression. Additionally, mouse AR expression and activity correlated well with AR expression inhuman tissues. The anti-androgen bicalutamide reduced luciferase signal in all tissues. Our model demonstrates thatandrogens can act in these tissues directly via AR, rather than exclusively via androgen aromatisation to estrogensand activation of the estrogen receptor. Additionally, it visually demonstrates the fundamental importance of ARsignalling outside the normal role in the reproductive organs. This model represents an important tool forphysiological and developmental analysis of androgen signalling, and for characterization of known and novelandrogenic or antiandrogenic compounds.
Frampton AE, Fletcher CE, Gall TMH, et al., 2013, Circulating peripheral blood mononuclear cells exhibit altered miRNA expression patterns in pancreatic cancer, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 13, Pages: 425-430, ISSN: 1473-7159
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- Citations: 19
Sita-Lumsden A, Dart DA, Waxman J, et al., 2013, Circulating microRNAs as potential new biomarkers for prostate cancer, British Journal of Cancer, Vol: 108, Pages: 1925-1930, ISSN: 1532-1827
Since they were first described in the 1990s, circulating microRNAs (miRNAs) have provided an active and rapidly evolving area of current research that has the potential to transform cancer diagnostics and therapeutics. In particular, miRNAs could provide potential new biomarkers for prostate cancer, the most common cause of cancer in UK men. Current diagnostic tests for prostate cancer have low specificity and poor sensitivity. Further, although many prostate cancers are so slow growing as not to pose a major risk to health, there is currently no test to distinguish between these and cancers that will become aggressive and life threatening. Circulating miRNAs are highly stable and are both detectable and quantifiable in a range of accessible bio fluids, thus have the potential to be useful diagnostic, prognostic and predictive biomarkers. This review aims to summarise the current understanding of circulating miRNAs in prostate cancer patients and their potential role as biomarkers.
Cano LQ, Lavery DN, Bevan CL, 2013, Mini-review: Foldosome regulation of androgen receptor action in prostate cancer, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 369, Pages: 52-62, ISSN: 0303-7207
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- Citations: 44
Dart DA, Brooke GN, Sita-Lumsden A, et al., 2012, Reducing prohibitin increases histone acetylation, and promotes androgen independence in prostate tumours by increasing androgen receptor activation by adrenal androgens, ONCOGENE, Vol: 31, Pages: 4588-4598, ISSN: 0950-9232
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- Citations: 18
Reebye V, Cano LQ, Lavery DN, et al., 2012, Role of the HSP90-Associated Cochaperone p23 in Enhancing Activity of the Androgen Receptor and Significance for Prostate Cancer, MOLECULAR ENDOCRINOLOGY, Vol: 26, Pages: 1694-1706, ISSN: 0888-8809
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- Citations: 27
Fletcher CE, Dart DA, Sita-Lumsden A, et al., 2012, Androgen-regulated processing of the oncomir MiR-27a, which targets Prohibitin in prostate cancer, HUMAN MOLECULAR GENETICS, Vol: 21, Pages: 3112-3127, ISSN: 0964-6906
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- Citations: 117
Grosdidier S, Carbo LR, Buzon V, et al., 2012, Allosteric Conversation in the Androgen Receptor Ligand-Binding Domain Surfaces, MOLECULAR ENDOCRINOLOGY, Vol: 26, Pages: 1078-1090, ISSN: 0888-8809
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- Citations: 52
Brooke GN, Bevan CL, Rudraraju B, et al., 2011, The RNA Binding Protein FUS Is a Potential Marker for Breast Cancer Progression and Therapy Response., CANCER RESEARCH, Vol: 71, ISSN: 0008-5472
Teahan O, Bevan CL, Waxman J, et al., 2011, Metabolic signatures of malignant progression in prostate epithelial cells, INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, Vol: 43, Pages: 1002-1009, ISSN: 1357-2725
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- Citations: 40
Lavery DN, Villaronga MA, Walker MM, et al., 2011, Repression of Androgen Receptor Activity by HEYL, a Third Member of the Hairy/Enhancer-of-split-related Family of Notch Effectors, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 17796-17808
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- Citations: 34
Brooke GN, Culley RL, Dart DA, et al., 2011, FUS/TLS Is a Novel Mediator of Androgen-Dependent Cell-Cycle Progression and Prostate Cancer Growth, CANCER RESEARCH, Vol: 71, Pages: 914-924, ISSN: 0008-5472
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- Citations: 52
Lavery DN, Bevan CL, 2011, Androgen Receptor Signalling in Prostate Cancer: The Functional Consequences of Acetylation, Journal of Biomedicine and Biotechnology, Vol: 2011, ISSN: 1110-7251
The androgen receptor (AR) is a ligand activated transcription factor and member of the steroid hormone receptor (SHR) subfamily of nuclear receptors. In the early stages of prostate carcinogenesis, tumour growth is dependent on androgens, and AR directly mediates these effects by modulating gene expression. During transcriptional regulation, the AR recruits numerous cofactors with acetylation-modifying enzymatic activity, the best studied include p300/CBP and the p160/SRC family of coactivators. It is known that recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) is key in fine-tuning responses to androgens and is thus likely to play a role in prostate cancer progression. Further, these proteins can also modify the AR itself. The functional consequences of AR acetylation, the role of modifying enzymes in relation to AR transcriptional response, and prostate cancer will be discussed.
Reebye V, Bevan CL, Nohadani M, et al., 2010, Interaction between AR signalling and CRKL bypasses casodex inhibition in prostate cancer, CELLULAR SIGNALLING, Vol: 22, Pages: 1874-1881, ISSN: 0898-6568
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- Citations: 4
Dart DA, Fletcher C, Bevan CL, 2010, Inhibiting androgen receptor activity in prostate cancer by cofactor manipulation, 21st Meeting of the European-Association-for-Cancer-Research, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 32-33, ISSN: 1359-6349
Villaronga MA, Lavery DN, Bevan CL, et al., 2010, HEY1 Leu94Met gene polymorphism dramatically modifies its biological functions, ONCOGENE, Vol: 29, Pages: 411-420, ISSN: 0950-9232
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- Citations: 22
Dart DA, Spencer-Dene B, Gamble SC, et al., 2009, Manipulating prohibitin levels provides evidence for an <i>in vivo</i> role in androgen regulation of prostate tumours, ENDOCRINE-RELATED CANCER, Vol: 16, Pages: 1157-1169, ISSN: 1351-0088
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- Citations: 43
Brooke GN, Bevan CL, 2009, The role of androgen receptor mutations in prostate cancer progression, Current Genomics, Vol: 10, Pages: 18-25, ISSN: 1389-2029
Prostate tumour growth is almost always dependent upon the androgen receptor pathway and hence therapies aimed at blocking this signalling axis are useful tools in the management of this disease. Unfortunately such therapies invariably fail; and the tumour progresses to an “androgen-independent” stage. In such cases androgen receptor expression is almost always maintained and much evidence exists to suggest that it may still be driving growth. One mechanism by which the receptor is thought to remain active is mutation. This review summarises the present data on androgen receptor mutations in prostate cancer, and how such substitutions offer a growth advantage by affecting cofactor interactions or by reducing ligand specificity. Such alterations appear to have a subsequent effect upon gene expression suggesting that tumours may “behave” differently dependent upon the ligand promoting growth and if a mutation is present.
Villaronga MA, Bevan CL, Belandia B, 2008, Notch Signaling: A Potential Therapeutic Target in Prostate Cancer, CURRENT CANCER DRUG TARGETS, Vol: 8, Pages: 566-580, ISSN: 1568-0096
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- Citations: 42
Balkwill F, Bevan C, Burfitt M, et al., 2008, Delivering Innovative Cancer Diagnostics and Treatments to Patients
Brooke GN, Parker MG, Bevan CL, 2008, Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression, ONCOGENE, Vol: 27, Pages: 2941-2950, ISSN: 0950-9232
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- Citations: 63
Appleby J, Balkwill F, Bevan C, et al., 2007, Cancer Vision 2025: The Science Pathway to Effective Treatments and Services
Chang GTG, Gamble SC, Jhamai M, et al., 2007, Proteomic analysis of proteins regulated by TRPS1 transcription factor in DU145 prostate cancer cells, BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, Vol: 1774, Pages: 575-582, ISSN: 1570-9639
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- Citations: 12
Gamble SC, Chotai D, Odontiadis M, et al., 2007, Prohibitin, a protein downregulated by androgens, represses androgen receptor activity, ONCOGENE, Vol: 26, Pages: 1757-1768, ISSN: 0950-9232
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- Citations: 62
Powell SM, Brooke GN, Whitaker HC, et al., 2006, Mechanisms of androgen receptor repression in prostate cancer, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 34, Pages: 1124-1127, ISSN: 0300-5127
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- Citations: 14
Teahan O, Gamble S, Holmes E, et al., 2006, Impact of analytical bias in metabonomic studies of human blood serum and plasma, ANALYTICAL CHEMISTRY, Vol: 78, Pages: 4307-4318, ISSN: 0003-2700
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- Citations: 205
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