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N Tufton Centre for Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
Department of Endocrinology, St Bartholomew’s Hospital, Barts Health NHS Trust. West Smithfield, London, UK

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R J Hearnden Centre for Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK

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D M Berney Department of Pathology, Royal London Hospital, Whitechapel, London, UK

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W M Drake Centre for Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
Department of Endocrinology, St Bartholomew’s Hospital, Barts Health NHS Trust. West Smithfield, London, UK

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L Parvanta Department of Endocrine Surgery, St Bartholomew’s Hospital, Barts Health NHS Trust, West Smithfield, London, UK

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J P Chapple Centre for Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK

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S A Akker Centre for Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
Department of Endocrinology, St Bartholomew’s Hospital, Barts Health NHS Trust. West Smithfield, London, UK

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Emerging evidence suggests the composition of the tumour microenvironment (TME) correlates with clinical outcome and that each tumour type has a unique TME including a variable population of inflammatory cells. We performed immunohistochemistry on 65 phaeochromocytoma and paraganglioma (PPGL) tumour samples with 20 normal adrenal medulla samples for comparison. The immune cells assessed were macrophages, lymphocytes and neutrophils, and we compared the proportion of infiltration of these immune cells with clinical and histopathological factors. There was a higher proportion of immune cells in tumour tissue compared to non-neoplastic adrenal medulla tissue, with a predominance of macrophages. There was a higher proportion of M2:M1 macrophages and T-helper lymphocytes in aggressive tumours compared to indolent ones. For SDHB-associated tumours, there was a higher proportion of M2 macrophage infiltration, with higher M2:M1 in aggressive SDHB PPGLs compared to indolent tumours. These data demonstrate that immune cells do infiltrate the TME of PPGLs, confirming that PPGLs are immunologically active tumours. Differences in the TME of PPGLs were observed between aggressive and indolent tumours. These differences could potentially be exploited as an aid in predicting tumour behaviour.

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Marie-Claude Hofmann Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Muthusamy Kunnimalaiyaan Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Jennifer R Wang Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Naifa L Busaidy Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Steven I Sherman Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Stephen Y Lai Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Mark Zafereo Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Maria E Cabanillas Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Protein kinases play critical roles in cell survival, proliferation, and motility. Their dysregulation is therefore a common feature in the pathogenesis of a number of solid tumors, including thyroid cancers. Inhibiting activated protein kinases has revolutionized thyroid cancer therapy, offering a promising strategy in treating tumors refractory to radioactive iodine treatment or cytotoxic chemotherapies. However, despite satisfactory early responses, these drugs are not curative and most patients inevitably progress due to drug resistance. This review summarizes up-to-date knowledge on various mechanisms that thyroid cancer cells develop to bypass protein kinase inhibition and outlines strategies that are being explored to overcome drug resistance. Understanding how cancer cells respond to drugs and identifying novel molecular targets for therapy still represents a major challenge for the treatment of these patients.

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Sasha R Howard Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
Department of Paediatric Endocrinology, Barts Health NHS Trust, London, UK

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Sarah Freeston Whipps Cross Hospital, Barts Health NHS Trust, London, UK

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Barney Harrison Retired Endocrine Surgeon, Sheffield, UK

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Louise Izatt Department of Clinical and Cancer Genetics, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

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Sonali Natu Department of Pathology, University Hospital of North Tees and Hartlepool NHS Foundation Trust, Stockton-on-Tees, UK

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Kate Newbold Department of Clinical Oncology, Royal Marsden Hospital Foundation Trust, London, UK

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Sabine Pomplun Department of Pathology, University College London Hospital NHS Foundation Trust, London, UK

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Helen A Spoudeas Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

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Sophie Wilne Department of Paediatric Oncology, Nottingham University Hospital’s NHS Trust, Nottingham, UK

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Tom R Kurzawinski Department of Endocrine Surgery, University College London Hospitals NHS Foundation Trust, London, UK
Department of Paediatric Endocrine Surgery, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

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Mark N Gaze Department of Clinical Oncology, University College London Hospitals NHS Foundation Trust, London, UK
Department of Clinical Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

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This guideline is written as a reference document for clinicians presented with the challenge of managing paediatric patients with differentiated thyroid carcinoma up to the age of 19 years. Care of paediatric patients with differentiated thyroid carcinoma differs in key aspects from that of adults, and there have been several recent developments in the care pathways for this condition; this guideline has sought to identify and attend to these areas. It addresses the presentation, clinical assessment, diagnosis, management (both surgical and medical), genetic counselling, follow-up and prognosis of affected patients. The guideline development group formed of a multi-disciplinary panel of sub-speciality experts carried out a systematic primary literature review and Delphi Consensus exercise. The guideline was developed in accordance with The Appraisal of Guidelines Research and Evaluation Instrument II criteria, with input from stakeholders including charities and patient groups. Based on scientific evidence and expert opinion, 58 recommendations have been collected to produce a clear, pragmatic set of management guidelines. It is intended as an evidence base for future optimal management and to improve the quality of clinical care of paediatric patients with differentiated thyroid carcinoma.

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Masaki Shiota Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Shusuke Akamatsu Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Shigehiro Tsukahara Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Shohei Nagakawa Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Takashi Matsumoto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Masatoshi Eto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. However, treatment resistance emerges after hormonal manipulation in most prostate cancers, and it is attributable to a number of mechanisms, including AR amplification and overexpression, AR mutations, the expression of constitutively active AR variants, intra-tumor androgen synthesis, and promiscuous AR activation by other factors. Although various AR mutations have been reported in prostate cancer, specific AR mutations (L702H, W742L/C, H875Y, F877L, and T878A/S) were frequently identified after treatment resistance emerged. Intriguingly, these hot spot mutations were also revealed to change the binding affinity of ligands including steroids and antiandrogens and potentially result in altered responses to AR pathway inhibitors. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Since clinical data between AR mutations and the efficacy of AR pathway inhibitors are accumulating, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy. However, there are few reviews on clinical significance of AR hot spot mutations in prostate cancer. Then, this review summarized the clinical landscape of AR mutations and discussed their potential implication for clinical utilization.

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Maria Eugenia Sabatino Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina

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Juan Pablo Petiti Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina

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Liliana del Valle Sosa Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina

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Pablo Anibal Pérez Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina

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Silvina Gutiérrez Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina

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Carolina Leimgruber Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina

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Alexandra Latini Laboratorio de Bioenergética y Estrés Oxidativo, Departamento de Bioquímica, Centro de Ciencias Biológicas, Florianópolis, Brazil

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Alicia Inés Torres Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina

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Ana Lucía De Paul Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
Instituto de Investigaciones en Ciencias de la Salud (INICSA–CONICET), Córdoba, Argentina

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Kreepa G Kooblall OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Victoria J Stokes OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Omair A Shariq OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Katherine A English OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Mark Stevenson OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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John Broxholme Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK

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Benjamin Wright Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK

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Helen E Lockstone Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK

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David Buck Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK

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Simona Grozinsky-Glasberg Neuroendocrine Tumor Unit, ENETS Center of Excellence, Endocrinology & Metabolism Department, Hadassah Medical Center and Faculty of Medicine, The Hebrew University of Jerusalem, Israel

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Christopher J Yates OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Rajesh V Thakker OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK

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Kate E Lines OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Multiple endocrine neoplasia type 1 (MEN1), caused by mutations in the MEN1 gene encoding menin, is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic neuroendocrine tumours (NETs). Development of these tumours is associated with wide variations in their severity, order and ages (from <5 to >80 years), requiring life-long screening. To improve tumour surveillance and quality of life, better circulating biomarkers, particularly for pancreatic NETs that are associated with higher mortality, are required. We, therefore, examined the expression of circulating miRNA in the serum of MEN1 patients. Initial profiling analysis followed by qRT-PCR validation studies identified miR-3156-5p to be significantly downregulated (−1.3 to 5.8-fold, P < 0.05–0.0005) in nine MEN1 patients, compared to matched unaffected relatives. MEN1 knock-down experiments in BON-1 human pancreatic NET cells resulted in reduced MEN1 (49%, P < 0.05), menin (54%, P < 0.05) and miR-3156-5p expression (20%, P < 0.005), compared to control-treated cells, suggesting that miR-3156-5p downregulation is a consequence of loss of MEN1 expression. In silico analysis identified mortality factor 4-like 2 (MOR4FL2) as a potential target of miR-3156-5p, and in vitro functional studies in BON-1 cells transfected with either miR-3156-5p mimic or inhibitors showed that the miR-3156-5p mimic significantly reduced MORF4L2 protein expression (46%, P < 0.005), while miR-3156-5p inhibitor significantly increased MORF4L2 expression (1.5-fold, P < 0.05), compared to control-treated cells, thereby confirming that miR-3156-5p regulates MORF4L2 expression. Thus, the inverse relationship between miR-3156-5p and MORF4L2 expression represents a potential serum biomarker that could facilitate the detection of NET occurrence in MEN1 patients.

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Paul Benjamin Loughrey Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, UK
Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, UK

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Federico Roncaroli Geoffrey Jefferson Brain Research Centre, Division of Neuroscience and Experimental Psychology, School of Medicine, Manchester University, Manchester, UK

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Estelle Healy Department of Cellular Pathology, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, UK

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Philip Weir Department of Neurosurgery, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, UK

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Madhu Basetti Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK

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Ruth T Casey Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

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Steven J Hunter Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, UK

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Márta Korbonits Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Pituitary neuroendocrine tumours (PitNETs) associated with paragangliomas or phaeochromocytomas are rare. SDHx variants are estimated to be associated with 0.3–1.8% of PitNETs. Only a few case reports have documented the association with MAX variants. Prolactinomas are the most common PitNETs occurring in patients with SDHx variants, followed by somatotrophinomas, clinically non-functioning tumours and corticotrophinomas. One pituitary carcinoma has been described. SDHC, SDHB and SDHA mutations are inherited in an autosomal dominant fashion and tumorigenesis seems to adhere to Knudson’s two-hit hypothesis. SDHD and SDHAF2 mutations most commonly have paternal inheritance. Immunohistochemistry for SDHB or MAX and loss of heterozygosity analysis can support the assessment of pathogenicity of the variants. Metabolomics is promising in the diagnosis of SDHx-related disease. Future research should aim to further clarify the role of SDHx and MAX variants or other genes in the molecular pathogenesis of PitNETs, including pseudohypoxic and kinase signalling pathways along with elucidating epigenetic mechanisms to predict tumour behaviour.

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Manuel D Gahete Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
Reina Sofía University Hospital, Córdoba, Spain
CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain

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Natalia Herman-Sanchez Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
Reina Sofía University Hospital, Córdoba, Spain
CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain

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Antonio C Fuentes-Fayos Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
Reina Sofía University Hospital, Córdoba, Spain
CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain

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Juan L Lopez-Canovas Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
Reina Sofía University Hospital, Córdoba, Spain
CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain

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Raúl M Luque Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
Reina Sofía University Hospital, Córdoba, Spain
CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain

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The dysregulation of the splicing process has emerged as a novel hallmark of metabolic and tumor pathologies. In breast cancer (BCa), which represents the most diagnosed cancer type among women worldwide, the generation and/or dysregulation of several oncogenic splicing variants have been described. This is the case of the splicing variants of HER2, ER, BRCA1, or the recently identified by our group, In1-ghrelin and SST5TMD4, which exhibit oncogenic roles, increasing the malignancy, poor prognosis, and resistance to treatment of BCa. This altered expression of oncogenic splicing variants has been closely linked with the dysregulation of the elements belonging to the macromolecular machinery that controls the splicing process (spliceosome components and the associated splicing factors). In this review, we compile the current knowledge demonstrating the altered expression of splicing variants and spliceosomal components in BCa, showing the existence of a growing body of evidence supporting the close implication of the alteration in the splicing process in mammary tumorigenesis.

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Anastasia Alataki Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital and The Institute of Cancer Research, London, UK
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK

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Mitch Dowsett Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital and The Institute of Cancer Research, London, UK
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK

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Endocrine therapies are the main treatment strategies for the clinical management of hormone-dependent breast cancer. Despite prolonged time to recurrence in the adjuvant setting and the initial clinical responses in the metastatic setting, many patients eventually encounter tumour relapse due to acquired resistance to these agents. Other patients experience a lack of tumour regression at the beginning of treatment indicating de novo resistance that significantly limits its efficacy in the clinic. There is compelling evidence that human epidermal growth factor receptor-2 (HER2) overexpression contributes to resistance to endocrine therapies in oestrogen receptor-positive (ER+) breast cancer. ER+/HER2+ tumours comprise about 10% of all breast cancer cases and about 60% of the whole set of HER2+ tumours. Most patients with primary ER+/HER2+ disease will receive antibody-based HER2-targeted therapy, but this is generally for no more than one year while endocrine treatment is usually for at least 5 years. A number of HER2-kinase inhibitors are also now in clinical use or in clinical trials, and the interaction of these with endocrine treatment may differ from that of antibody treatment. In this review article, we aim to summarise knowledge on molecular mechanisms of breast cancer resistance to endocrine therapies attributable to the impact of HER2 signalling on endocrine sensitivity, to discuss data from clinical trials addressing the role of HER2 in the development of endocrine resistance in the metastatic, neoadjuvant and adjuvant settings and to explore rational new therapeutic strategies.

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Adriana Albani Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Luis Gustavo Perez-Rivas Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Sicheng Tang Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Julia Simon Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Kristin Elisabeth Lucia Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Paula Colón-Bolea Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Jochen Schopohl Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Sigrun Roeber Center for Neuropathology and Prion Research, LMU Munich, Munich, Germany

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Michael Buchfelder Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen, Germany

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Roman Rotermund Department of Neurosurgery, Universitätskrankenhaus Hamburg-Eppendorf, Hamburg, Germany

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Jörg Flitsch Department of Neurosurgery, Universitätskrankenhaus Hamburg-Eppendorf, Hamburg, Germany

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Jun Thorsteinsdottir Neurochirurgische Klinik und Poliklinik, LMU Klinikum, Munich, Germany

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Jochen Herms Center for Neuropathology and Prion Research, LMU Munich, Munich, Germany

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Günter Stalla Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
Medicover Neuroendocrinology, Munich, Germany

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Martin Reincke Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Marily Theodoropoulou Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Cushing’s disease is a rare but devastating and difficult to manage condition. The somatostatin analogue pasireotide is the only pituitary-targeting pharmaceutical approved for the treatment of Cushing’s disease but is accompanied by varying efficacy and potentially severe side effects. Finding means to predict which patients are more likely to benefit from this treatment may improve their management. More than half of corticotroph tumours harbour mutations in the USP8 gene, and there is evidence of higher somatostatin receptor 5 (SSTR5) expression in the USP8-mutant tumours. Pasireotide has a high affinity for SSTR5, indicating that these tumours may be more sensitive to treatment. To test this hypothesis, we examined the inhibitory action of pasireotide on adrenocorticotrophic hormone synthesis in primary cultures of human corticotroph tumour with assessed USP8 mutational status and in immortalized murine corticotroph tumour cells overexpressing human USP8 mutants frequent in Cushing’s disease. Our in vitro results demonstrate that pasireotide exerts a higher antisecretory response in USP8-mutant corticotroph tumours. Overexpressing USP8 mutants in a murine corticotroph tumour cell model increased endogenous somatostatin receptor 5 (Sstr5) transcription. The murine Sstr5 promoter has two binding sites for the activating protein 1 (AP-1) and USP8 mutants possibly to mediate their action by stimulating AP-1 transcriptional activity. Our data corroborate the USP8 mutational status as a potential marker of pasireotide response and describe a potential mechanism through which USP8 mutants may regulate SSTR5 gene expression.

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