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Aguilar H.,Catalan Institute of Nanoscience and Nanotechnology | Sole X.,Catalan Institute of Nanoscience and Nanotechnology | Bonifaci N.,Catalan Institute of Nanoscience and Nanotechnology | Serra-Musach J.,Catalan Institute of Nanoscience and Nanotechnology | And 7 more authors.
Oncogene | Year: 2010

Endocrine therapies targeting the proliferative effect of 17Β-estradiol through estrogen receptor α (ERα) are the most effective systemic treatment of ERα-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERα. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERα transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)-to pS167-ERα were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERα-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy. © 2010 Macmillan Publishers Limited All rights reserved. Source

Masson-Lecomte A.,Genetic and Molecular Epidemiology Group | Masson-Lecomte A.,French Institute of Health and Medical Research | Rava M.,Genetic and Molecular Epidemiology Group | Real F.X.,Epithelial Carcinogenesis Group | And 5 more authors.
European Urology | Year: 2014

Context Host immune response has an impact on tumour development and progression. There is interest in the use of inflammatory biomarkers (InfBMs) in cancer care. Although several studies assessing the potential prognostic value of InfBMs in cancer have been published in the past decades, they have had no impact on the management of patients with urothelial bladder carcinoma (UBC).Objective To review and summarise the scientific literature on the prognostic value of tumour, serum, urine, and germline DNA InfBMs on UBC. Evidence acquisition A systematic review of the literature was performed searching the Medline and Embase databases for original articles published between January 1975 and November 2013. The main inclusion criterion was the provision of a survival analysis (Kaplan-Meier and/or Cox) according to the Reporting Recommendations for Tumor Marker Prognostic Studies guidelines for the assessment of prognostic markers. We focused on markers assessed at least twice in the literature. Findings are reported following Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Evidence synthesis Overall, 34 publications, mostly retrospective, fulfilled the main inclusion criterion. Main limitations of these studies were missing relevant information about design or analysis and heterogeneous methodology used. Inflammatory cells, costimulatory molecules in tumour cells, and serum cytokines showed prognostic significance, mainly in univariable analyses. High C-reactive protein values were consistently reported as an independent prognostic factor for mortality in invasive UBC.Conclusions There is a dearth of studies on InfBMs in UBC compared with other tumour types. Evidence suggests that InfBMs may have an impact on the management of patients with UBC. Currently, methodological drawbacks of the studies limit the translational potential of results.Patient summary In this review, we analysed studies evaluating the impact of inflammatory response on bladder cancer progression. Despite methodological limitations, some inflammatory biomarkers should be further analysed because they hold promise to improve patient care. © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. Source

Gerlinger M.,Institute of Cancer Research | Catto J.W.,University of Sheffield | Orntoft T.F.,Aarhus University Hospital | Real F.X.,Epithelial Carcinogenesis Group | And 4 more authors.
European Urology | Year: 2015

Context Intratumour heterogeneity (ITH) can impair the precise molecular analysis of tumours and may contribute to difficulties encountered in cancer biomarker qualification and treatment personalisation. Objective This review summarises the evidence for genetic ITH in renal, bladder, and prostate carcinomas and potential strategies to address the clinical and translational research challenges arising from ITH. Evidence acquisition Publications that assessed ITH in the relevant urologic cancers were identified in a literature review. Evidence synthesis ITH with functionally distinct tumour subclones has been identified in all three tumour types. Heterogeneity of actionable genetic changes and of prognostic biomarkers between different tumour regions in the same patient suggests limitations of single biopsy-based molecular analyses for precision medicine approaches. Evolutionary constraints may differ between patients and may allow the prediction of specific evolutionary trajectories. Conclusions Assessment of multiple tumour regions for precision medicine purposes, monitoring of subclonal dynamics over time, and the preferential targeting of genetic alterations located on the trunk of the phylogenetic tree of individual cancers may accelerate the development of personalised medicine strategies and improve our understanding of treatment failure. Patient summary Genetic alterations can be heterogeneous within urologic tumours, complicating their use as biomarkers for treatment personalisation. We present novel strategies to address these challenges. © 2014 European Association of Urology. All rights reserved. Source

Ferrer J.,Imperial College London | Ferrer J.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Real F.X.,Epithelial Carcinogenesis Group | Real F.X.,University Pompeu Fabra
EMBO Journal | Year: 2016

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating human diseases. There is consequently a pressing need to understand its molecular underpinnings, which should enable new preventive and therapeutic strategies. A new study in The EMBO Journal (Diaferia et al, 2016) maps the transcriptome and epigenetic landscape associated with distinct PDAC grades and identifies cis- and trans-regulatory elements in tumour progression. A new genomewide study identifies cis- and trans-regulatory elements in pancreatic ductal carcinoma, thus shedding light on the mechanisms underlying tumour progression. © 2016 The Authors. Source

Malats N.,Genetic and Molecular Epidemiology Group | Real F.X.,Epithelial Carcinogenesis Group | Real F.X.,University Pompeu Fabra
Hematology/Oncology Clinics of North America | Year: 2015

Bladder cancer incidence is higher in old men, shows geographic variation, and is mostly an environmental disease. Cigarette smoking, occupational exposures, water arsenic, Schistosoma haematobium infestation, and some medications are the best established risk factors. Low-penetrance genetic factors also contribute to its origin, some through interaction with environmental factors. Bladder cancer has high prevalence and a low mortality, being largely a chronic disease. Data on environmental and genetic factors involved in the disease outcome are inconclusive. © 2015 Elsevier Inc. Source

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