ALBERT

Description: Suppression of BRCA1 sensitizes cells to proteasome inhibitors Cell Death and Disease 5, e1580 (December 2014). doi:10.1038/cddis.2014.537 Authors: Y Gu, P Bouwman, D Greco, J Saarela, B Yadav, J Jonkers & S G Kuznetsov

Description: Metastatic disease remains the primary cause of death for patients with breast cancer. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation. However, the precise contribution of tumour-induced systemic inflammation to metastasis and the mechanisms regulating systemic inflammation are poorly understood. Here we show that tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. We mechanistically demonstrate that interleukin (IL)-1beta elicits IL-17 expression from gamma delta (gammadelta) T cells, resulting in systemic, granulocyte colony-stimulating factor (G-CSF)-dependent expansion and polarization of neutrophils in mice bearing mammary tumours. Tumour-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, which limit the establishment of metastases. Neutralization of IL-17 or G-CSF and absence of gammadelta T cells prevents neutrophil accumulation and downregulates the T-cell-suppressive phenotype of neutrophils. Moreover, the absence of gammadelta T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumour progression. Our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system--the gammadelta T cell/IL-17/neutrophil axis--represents a new strategy to inhibit metastatic disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475637/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475637/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Coffelt, Seth B -- Kersten, Kelly -- Doornebal, Chris W -- Weiden, Jorieke -- Vrijland, Kim -- Hau, Cheei-Sing -- Verstegen, Niels J M -- Ciampricotti, Metamia -- Hawinkels, Lukas J A C -- Jonkers, Jos -- de Visser, Karin E -- 11-0677/Worldwide Cancer Research/United Kingdom -- 615300/European Research Council/International -- England -- Nature. 2015 Jun 18;522(7556):345-8. doi: 10.1038/nature14282. Epub 2015 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands. ; 1] Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2300 RC, The Netherlands [2] Centre for Biomedical Genetics, Leiden University Medical Center, Albinusdreef 2, Leiden, 2300 RC, The Netherlands. ; Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25822788" target="_blank"〉PubMed〈/a〉

Description: Since its discovery in the early 1990s the deleted in colorectal cancer (DCC) gene, located on chromosome 18q21, has been proposed as a tumour suppressor gene as its loss is implicated in the majority of advanced colorectal and many other cancers. DCC belongs to the family of netrin 1 receptors, which function as dependence receptors as they control survival or apoptosis depending on ligand binding. However, the role of DCC as a tumour suppressor remains controversial because of the rarity of DCC-specific mutations and the presence of other tumour suppressor genes in the same chromosomal region. Here we show that in a mouse model of mammary carcinoma based on somatic inactivation of p53, additional loss of DCC promotes metastasis formation without affecting the primary tumour phenotype. Furthermore, we demonstrate that in cell cultures derived from p53-deficient mouse mammary tumours DCC expression controls netrin-1-dependent cell survival, providing a mechanistic basis for the enhanced metastatic capacity of tumour cells lacking DCC. Consistent with this idea, in vivo tumour-cell survival is enhanced by DCC loss. Together, our data support the function of DCC as a context-dependent tumour suppressor that limits survival of disseminated tumour cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krimpenfort, Paul -- Song, Ji-Ying -- Proost, Natalie -- Zevenhoven, John -- Jonkers, Jos -- Berns, Anton -- England -- Nature. 2012 Feb 22;482(7386):538-41. doi: 10.1038/nature10790.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22358843" target="_blank"〉PubMed〈/a〉

Description: We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nik-Zainal, Serena -- Davies, Helen -- Staaf, Johan -- Ramakrishna, Manasa -- Glodzik, Dominik -- Zou, Xueqing -- Martincorena, Inigo -- Alexandrov, Ludmil B -- Martin, Sancha -- Wedge, David C -- Van Loo, Peter -- Ju, Young Seok -- Smid, Marcel -- Brinkman, Arie B -- Morganella, Sandro -- Aure, Miriam R -- Lingjaerde, Ole Christian -- Langerod, Anita -- Ringner, Markus -- Ahn, Sung-Min -- Boyault, Sandrine -- Brock, Jane E -- Broeks, Annegien -- Butler, Adam -- Desmedt, Christine -- Dirix, Luc -- Dronov, Serge -- Fatima, Aquila -- Foekens, John A -- Gerstung, Moritz -- Hooijer, Gerrit K J -- Jang, Se Jin -- Jones, David R -- Kim, Hyung-Yong -- King, Tari A -- Krishnamurthy, Savitri -- Lee, Hee Jin -- Lee, Jeong-Yeon -- Li, Yilong -- McLaren, Stuart -- Menzies, Andrew -- Mustonen, Ville -- O'Meara, Sarah -- Pauporte, Iris -- Pivot, Xavier -- Purdie, Colin A -- Raine, Keiran -- Ramakrishnan, Kamna -- Rodriguez-Gonzalez, F German -- Romieu, Gilles -- Sieuwerts, Anieta M -- Simpson, Peter T -- Shepherd, Rebecca -- Stebbings, Lucy -- Stefansson, Olafur A -- Teague, Jon -- Tommasi, Stefania -- Treilleux, Isabelle -- Van den Eynden, Gert G -- Vermeulen, Peter -- Vincent-Salomon, Anne -- Yates, Lucy -- Caldas, Carlos -- Veer, Laura Van't -- Tutt, Andrew -- Knappskog, Stian -- Tan, Benita Kiat Tee -- Jonkers, Jos -- Borg, Ake -- Ueno, Naoto T -- Sotiriou, Christos -- Viari, Alain -- Futreal, P Andrew -- Campbell, Peter J -- Span, Paul N -- Van Laere, Steven -- Lakhani, Sunil R -- Eyfjord, Jorunn E -- Thompson, Alastair M -- Birney, Ewan -- Stunnenberg, Hendrik G -- van de Vijver, Marc J -- Martens, John W M -- Borresen-Dale, Anne-Lise -- Richardson, Andrea L -- Kong, Gu -- Thomas, Gilles -- Stratton, Michael R -- Nature. 2016 May 2. doi: 10.1038/nature17676.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. ; East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK. ; Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund SE-223 81, Sweden. ; Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, NM 87545, New Mexico, USA. ; Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. ; Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium. ; Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN, The Netherlands. ; Radboud University, Department of Molecular Biology, Faculty of Science, 6525GA Nijmegen, The Netherlands. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo 0310, Norway. ; K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway. ; Department of Computer Science, University of Oslo, Oslo, Norway. ; Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea. ; Translational Research Lab, Centre Leon Berard, 28, rue Laennec, 69373 Lyon Cedex 08, France. ; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. ; Breast Cancer Translational Research Laboratory, Universite Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium. ; Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. ; Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. ; Department of Pathology, Asan Medical Center, College of Medicine, Ulsan University, Ulsan, South Korea. ; Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, South Korea. ; Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. ; Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard., Houston, Texas 77030, USA. ; Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea. ; Institut National du Cancer, Research Division, Clinical Research Department, 52 avenue Morizet, 92513 Boulogne-Billancourt, France. ; University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming, Besancon 25000, France. ; Pathology Department, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. ; Oncologie Senologie, ICM Institut Regional du Cancer, Montpellier, France. ; The University of Queensland, UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland 4029, Australia. ; Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland. ; IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy. ; Department of Pathology, Centre Leon Berard, 28 rue Laennec, 69373 Lyon Cedex 08, France. ; Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium. ; Institut Curie, Paris Sciences Lettres University, Department of Pathology and INSERM U934, 26 rue d'Ulm, 75248 Paris Cedex 05, France. ; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. ; Breast Cancer Now Research Unit, King's College London, London SE1 9RT, UK. ; Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London SW3 6JB, UK. ; Department of Clinical Science, University of Bergen, 5020 Bergen, Norway. ; Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway. ; National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore. ; Singapore General Hospital, Outram Road, 169608, Singapore. ; Equipe Erable, INRIA Grenoble-Rhone-Alpes, 655, Avenue de l'Europe, 38330 Montbonnot-Saint Martin, France. ; Synergie Lyon Cancer, Centre Leon Berard, 28 rue Laennec, Lyon Cedex 08, France. ; Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas 77230, USA. ; Department of Radiation Oncology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands. ; Pathology Queensland, The Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia. ; Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27135926" target="_blank"〉PubMed〈/a〉

Description: Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671316/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Guotai -- Chapman, J Ross -- Brandsma, Inger -- Yuan, Jingsong -- Mistrik, Martin -- Bouwman, Peter -- Bartkova, Jirina -- Gogola, Ewa -- Warmerdam, Daniel -- Barazas, Marco -- Jaspers, Janneke E -- Watanabe, Kenji -- Pieterse, Mark -- Kersbergen, Ariena -- Sol, Wendy -- Celie, Patrick H N -- Schouten, Philip C -- van den Broek, Bram -- Salman, Ahmed -- Nieuwland, Marja -- de Rink, Iris -- de Ronde, Jorma -- Jalink, Kees -- Boulton, Simon J -- Chen, Junjie -- van Gent, Dik C -- Bartek, Jiri -- Jonkers, Jos -- Borst, Piet -- Rottenberg, Sven -- 090532/Wellcome Trust/United Kingdom -- 104558/Wellcome Trust/United Kingdom -- P30 CA016672/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2015 May 28;521(7553):541-4. doi: 10.1038/nature14328. Epub 2015 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. ; Department of Genetics, Erasmus, University Medical Center, 3000 CA Rotterdam, The Netherlands. ; Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech Republic. ; Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; Danish Cancer Society Research Center, 2100 Copenhagen, Denmark. ; Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; Protein Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; Deep Sequencing Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms, Hertfordshire EN6 3LD, UK. ; 1] Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech Republic [2] Danish Cancer Society Research Center, 2100 Copenhagen, Denmark. ; 1] Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands [2] Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Laengassstrasse 122, 3012 Bern, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799992" target="_blank"〉PubMed〈/a〉

Description: The aim of this study was to compare young and adult sprinters on several biomechanical parameters that were previously highlighted as performance-related and to determine the behaviour of several muscle–tendon units (MTU) in the first stance phase following a block start in sprint running. The ground reaction force (GRF) and kinematic data were collected from 16 adult and 21 young well-trained sprinters. No difference between the groups was found in some of the previously highlighted performance-related parameters (ankle joint stiffness, the range of dorsiflexion and plantar flexor moment). Interestingly, the young sprinters showed a greater maximal and mean ratio of horizontal to total GRF, which was mainly attributed to a greater horizontal GRF relative to body mass and resulted in a greater change in horizontal centre of mass (COM) velocity during the stance phase in the young compared with the adult sprinters. Results from the MTU length analyses showed that adult sprinters had more MTU shortening and higher maximal MTU shortening velocities in all plantar flexors and the rectus femoris. Although previously highlighted performance-related parameters could not explain the greater 100 m sprinting times in the adult sprinters, differences were found in the behaviour of the MTU of the plantar flexors and rectus femoris during the first stance phase. The pattern of length changes in these MTUs provides ideal conditions for the use of elastic energy storage and release for power enhancement.