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https://www.readbyqxmd.com/read/28729482/brca1-and-brca2-tumor-suppressors-protect-against-endogenous-acetaldehyde-toxicity
#1
Eliana Mc Tacconi, Xianning Lai, Cecilia Folio, Manuela Porru, Gijs Zonderland, Sophie Badie, Johanna Michl, Irene Sechi, Mélanie Rogier, Verónica Matía García, Ankita Sati Batra, Oscar M Rueda, Peter Bouwman, Jos Jonkers, Anderson Ryan, Bernardo Reina-San-Martin, Joannie Hui, Nelson Tang, Alejandra Bruna, Annamaria Biroccio, Madalena Tarsounas
Maintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR-compromised cells are sensitive to acetaldehyde, similarly to FANCD2-deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional...
July 20, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28714471/progression-through-mitosis-promotes-parp-inhibitor-induced-cytotoxicity-in-homologous-recombination-deficient-cancer-cells
#2
Pepijn M Schoonen, Francien Talens, Colin Stok, Ewa Gogola, Anne Margriet Heijink, Peter Bouwman, Floris Foijer, Madalena Tarsounas, Sohvi Blatter, Jos Jonkers, Sven Rottenberg, Marcel A T M van Vugt
Mutations in homologous recombination (HR) genes BRCA1 and BRCA2 predispose to tumorigenesis. HR-deficient cancers are hypersensitive to Poly (ADP ribose)-polymerase (PARP) inhibitors, but can acquire resistance and relapse. Mechanistic understanding how PARP inhibition induces cytotoxicity in HR-deficient cancer cells is incomplete. Here we find PARP inhibition to compromise replication fork stability in HR-deficient cancer cells, leading to mitotic DNA damage and consequent chromatin bridges and lagging chromosomes in anaphase, frequently leading to cytokinesis failure, multinucleation and cell death...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28650484/insertional-mutagenesis-identifies-drivers-of-a-novel-oncogenic-pathway-in-invasive-lobular-breast-carcinoma
#3
Sjors M Kas, Julian R de Ruiter, Koen Schipper, Stefano Annunziato, Eva Schut, Sjoerd Klarenbeek, Anne Paulien Drenth, Eline van der Burg, Christiaan Klijn, Jelle J Ten Hoeve, David J Adams, Marco J Koudijs, Jelle Wesseling, Micha Nethe, Lodewyk F A Wessels, Jos Jonkers
Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype and accounts for 8-14% of all cases. Although the majority of human ILCs are characterized by the functional loss of E-cadherin (encoded by CDH1), inactivation of Cdh1 does not predispose mice to develop mammary tumors, implying that mutations in additional genes are required for ILC formation in mice. To identify these genes, we performed an insertional mutagenesis screen using the Sleeping Beauty transposon system in mice with mammary-specific inactivation of Cdh1...
June 26, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28644128/intraductal-cisplatin-treatment-in-a-brca-associated-breast-cancer-mouse-model-attenuates-tumor-development-but-leads-to-systemic-tumors-in-aged-female-mice
#4
Jolien S de Groot, Paul J van Diest, Miranda van Amersfoort, Eva J Vlug, Xiaojuan Pan, Natalie D Ter Hoeve, Hilde Rosing, Jos H Beijnen, Sameh A Youssef, Alain de Bruin, Jos Jonkers, Elsken van der Wall, Patrick W B Derksen
BRCA deficiency predisposes to the development of invasive breast cancer. In BRCA mutation carriers this risk can increase up to 80%. Currently, bilateral prophylactic mastectomy and prophylactic bilateral salpingo-oophorectomy are the only preventive, albeit radical invasive strategies to prevent breast cancer in BRCA mutation carriers. An alternative non-invasive way to prevent BRCA1-associated breast cancer may be local prophylactic treatment via the nipple.Using a non-invasive intraductal (ID) preclinical intervention strategy, we explored the use of combined cisplatin and poly (ADP)-ribose polymerase 1 (PARP1) inhibition to prevent the development of hereditary breast cancer...
June 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28575524/identifying-transposon-insertions-and-their-effects-from-rna-sequencing-data
#5
Julian R de Ruiter, Sjors M Kas, Eva Schut, David J Adams, Marco J Koudijs, Lodewyk F A Wessels, Jos Jonkers
Insertional mutagenesis using engineered transposons is a potent forward genetic screening technique used to identify cancer genes in mouse model systems. In the analysis of these screens, transposon insertion sites are typically identified by targeted DNA-sequencing and subsequently assigned to predicted target genes using heuristics. As such, these approaches provide no direct evidence that insertions actually affect their predicted targets or how transcripts of these genes are affected. To address this, we developed IM-Fusion, an approach that identifies insertion sites from gene-transposon fusions in standard single- and paired-end RNA-sequencing data...
June 1, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28514727/nuclear-receptor-nr4a1-is-a-tumor-suppressor-down-regulated-in-triple-negative-breast-cancer
#6
Hongmei Wu, Jiong Bi, Yan Peng, Lei Huo, Xiaobin Yu, Zhihui Yang, Yunyun Zhou, Li Qin, Yixiang Xu, Lan Liao, Yang Xie, Orla M Conneely, Jos Jonkers, Jianming Xu
The nuclear receptor (NR) superfamily contains hormone-inducible transcription factors that regulate many physiological and pathological processes through regulating gene expression. NR4A1 is an NR family member that still does not have an identified endogenous ligand, and its role in cancer is also currently unclear and controversial. In this study, we aimed to define the expression profiles and specific role of NR4A1 in the highly malignant triple-negative breast cancer (TNBC), which still lacks available targeted therapies...
April 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28104906/interrogating-open-issues-in-cancer-precision-medicine-with-patient-derived-xenografts
#7
REVIEW
Annette T Byrne, Denis G Alférez, Frédéric Amant, Daniela Annibali, Joaquín Arribas, Andrew V Biankin, Alejandra Bruna, Eva Budinská, Carlos Caldas, David K Chang, Robert B Clarke, Hans Clevers, George Coukos, Virginie Dangles-Marie, S Gail Eckhardt, Eva Gonzalez-Suarez, Els Hermans, Manuel Hidalgo, Monika A Jarzabek, Steven de Jong, Jos Jonkers, Kristel Kemper, Luisa Lanfrancone, Gunhild Mari Mælandsmo, Elisabetta Marangoni, Jean-Christophe Marine, Enzo Medico, Jens Henrik Norum, Héctor G Palmer, Daniel S Peeper, Pier Giuseppe Pelicci, Alejandro Piris-Gimenez, Sergio Roman-Roman, Oscar M Rueda, Joan Seoane, Violeta Serra, Laura Soucek, Dominique Vanhecke, Alberto Villanueva, Emilie Vinolo, Andrea Bertotti, Livio Trusolino
Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions...
April 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28028012/genetically-engineered-mouse-models-in-oncology-research-and-cancer-medicine
#8
REVIEW
Kelly Kersten, Karin E de Visser, Martine H van Miltenburg, Jos Jonkers
Genetically engineered mouse models (GEMMs) have contributed significantly to the field of cancer research. In contrast to cancer cell inoculation models, GEMMs develop de novo tumors in a natural immune-proficient microenvironment. Tumors arising in advanced GEMMs closely mimic the histopathological and molecular features of their human counterparts, display genetic heterogeneity, and are able to spontaneously progress toward metastatic disease. As such, GEMMs are generally superior to cancer cell inoculation models, which show no or limited heterogeneity and are often metastatic from the start...
February 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27989384/evaluation-of-predicted-knee-function-for-component-malrotation-in-total-knee-arthroplasty
#9
Valentine Vanheule, Hendrik Pieter Delport, Michael Skipper Andersen, Lennart Scheys, Roel Wirix-Speetjens, Ilse Jonkers, Jan Victor, Jos Vander Sloten
Soft-tissue balancing for total knee arthroplasty (TKA) remains subjective and highly dependent on surgical expertise. Pre-operative planning may support the clinician in taking decisions by integrating subject-specific computer models that predict functional outcome. However, validation of these models is essential before they can be applied in clinical practice. The aim of this study was to evaluate a knee modelling workflow by comparing experimental cadaveric measures to model-based kinematics and ligament length changes...
February 2017: Medical Engineering & Physics
https://www.readbyqxmd.com/read/27943283/prophylactic-window-therapy-with-the-clinical-poly-adp-ribose-polymerase-inhibitor-olaparib-delays-brca1-deficient-mammary-tumour-formation-in-mice
#10
Marieke van de Ven, Eline van der Burg, Hanneke van der Gulden, Sjoerd Klarenbeek, Peter Bouwman, Jos Jonkers
Women with heterozygous germline mutations in the BRCA1 tumour suppressor gene are strongly predisposed to developing early-onset breast cancer through loss of the remaining wild-type BRCA1 allele and inactivation of TP53. Although tumour prevention strategies in BRCA1-mutation carriers are still limited to prophylactic surgery, several therapeutic strategies have been developed to target the DNA repair defects (also known as 'BRCAness') of BRCA1-deficient tumours. In particular, DNA-damaging agents such as platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors show strong activity against BRCA1-mutated tumours...
December 9, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/27815543/genetic-dissection-of-cancer-development-therapy-response-and-resistance-in-mouse-models-of-breast-cancer
#11
Stefano Annunziato, Marco Barazas, Sven Rottenberg, Jos Jonkers
The cancer genomics revolution has rapidly expanded the inventory of somatic mutations characterizing human malignancies, highlighting a previously underappreciated extent of molecular variability between and within patients. Also in breast cancer, the most commonly diagnosed malignancy in women, this heterogeneity complicates the understanding of the stepwise sequence of pathogenic events and the design of effective and long-lasting target therapies. To disentangle this complexity and pinpoint which molecular perturbations are crucial to hijack the cellular machinery and lead to tumorigenesis and drug resistance, functional studies are needed in model systems that faithfully and comprehensively recapitulate all the salient aspects of their cognate human counterparts...
November 4, 2016: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/27798604/lgr6-labels-a-rare-population-of-mammary-gland-progenitor-cells-that-are-able-to-originate-luminal-mammary-tumours
#12
Leander Blaas, Fabio Pucci, Hendrik A Messal, Agneta B Andersson, E Josue Ruiz, Marco Gerling, Iyadh Douagi, Bradley Spencer-Dene, Alexandra Musch, Richard Mitter, Leena Bhaw, Richard Stone, Dorothee Bornhorst, Abdul K Sesay, Jos Jonkers, Gordon Stamp, Ilaria Malanchi, Rune Toftgård, Axel Behrens
The mammary gland is composed of a complex cellular hierarchy with unusual postnatal plasticity. The identities of stem/progenitor cell populations, as well as tumour-initiating cells that give rise to breast cancer, are incompletely understood. Here we show that Lgr6 marks rare populations of cells in both basal and luminal mammary gland compartments in mice. Lineage tracing analysis showed that Lgr6(+) cells are unipotent progenitors, which expand clonally during puberty but diminish in adulthood. In pregnancy or following stimulation with ovarian hormones, adult Lgr6(+) cells regained proliferative potency and their progeny formed alveoli over repeated pregnancies...
December 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27680696/erratum-replication-fork-stability-confers-chemoresistance-in-brca-deficient-cells
#13
Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A Calvo, Nicholas J Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M Starnes, Julian R de Ruiter, Jeremy A Daniel, Panagiotis A Konstantinopoulos, David Cortez, Sharon B Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K Sharan, André Nussenzweig
No abstract text is available yet for this article.
November 17, 2016: Nature
https://www.readbyqxmd.com/read/27566577/secretome-proteomics-reveals-candidate-non-invasive-biomarkers-of-brca1-deficiency-in-breast-cancer
#14
Marc Warmoes, Siu W Lam, Petra van der Groep, Janneke E Jaspers, Yvonne H C M Smolders, Leon de Boer, Thang V Pham, Sander R Piersma, Sven Rottenberg, Epie Boven, Jos Jonkers, Paul J van Diest, Connie R Jimenez
Breast cancer arising in female BRCA1 mutation carriers is characterized by an aggressive phenotype and early age of onset. We performed tandem mass spectrometry-based proteomics of secretomes and exosome-like extracellular vesicles from BRCA1-deficient and BRCA1-proficient murine breast tumor models to identify extracellular protein biomarkers, which can be used as an adjunct to current diagnostic modalities in patients with BRCA1-deficient breast cancer. We identified 2,107 proteins, of which 215 were highly enriched in the BRCA1-deficient secretome...
September 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27550455/the-parp-inhibitor-azd2461-provides-insights-into-the-role-of-parp3-inhibition-for-both-synthetic-lethality-and-tolerability-with-chemotherapy-in-preclinical-models
#15
Lenka Oplustil O'Connor, Stuart L Rulten, Aaron N Cranston, Rajesh Odedra, Henry Brown, Janneke E Jaspers, Louise Jones, Charlotte Knights, Bastiaan Evers, Attilla Ting, Robert H Bradbury, Marina Pajic, Sven Rottenberg, Jos Jonkers, David Rudge, Niall M B Martin, Keith W Caldecott, Alan Lau, Mark J O'Connor
The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic...
October 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27524621/pten-loss-in-e-cadherin-deficient-mouse-mammary-epithelial-cells-rescues-apoptosis-and-results-in-development-of-classical-invasive-lobular-carcinoma
#16
Mirjam C Boelens, Micha Nethe, Sjoerd Klarenbeek, Julian R de Ruiter, Eva Schut, Nicola Bonzanni, Amber L Zeeman, Ellen Wientjens, Eline van der Burg, Lodewyk Wessels, Renée van Amerongen, Jos Jonkers
Invasive lobular carcinoma (ILC) is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary epithelium, we generated a mouse model of classical ILC (CLC), the main histological ILC subtype. While loss of E-cadherin induced cell dissemination and apoptosis, additional PTEN inactivation promoted cell survival and rapid formation of invasive mammary tumors that recapitulate the histological and molecular features, estrogen receptor (ER) status, growth kinetics, metastatic behavior, and tumor microenvironment of human CLC...
August 23, 2016: Cell Reports
https://www.readbyqxmd.com/read/27490433/understanding-human-immune-function-using-the-resources-from-the-human-functional-genomics-project
#17
Mihai G Netea, Leo A B Joosten, Yang Li, Vinod Kumar, Marije Oosting, Sanne Smeekens, Martin Jaeger, Rob Ter Horst, Melanie Schirmer, Hera Vlamakis, Richard Notebaart, Norman Pavelka, Raul Raul Aguirre-Gamboa, Morris A Swertz, Rahajeng N Tunjungputri, Wouter van de Heijden, Eric A Franzosa, Aylwin Ng, Daniel Graham, Kara Lassen, Kiki Schraa, Romana Netea-Maier, Jan Smit, Quirijn de Mast, Frank van de Veerdonk, Bart Jan Kullberg, Cees Tack, Inge van de Munckhof, Joost Rutten, Jacqueline van der Graaf, Lude Franke, Marten Hofker, Iris Jonkers, Mathieu Platteel, Astrid Maatman, Jingyuan Fu, Alexandra Zhernakova, Jos W M van der Meer, Charles A Dinarello, Andre van der Ven, Curtis Huttenhouwer, Hans Koenen, Irma Joosten, Ramnik J Xavier, Cisca Wijmenga
No abstract text is available yet for this article.
August 4, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27454287/brca1185delag-tumors-may-acquire-therapy-resistance-through-expression-of-ring-less-brca1
#18
Rinske Drost, Kiranjit K Dhillon, Hanneke van der Gulden, Ingrid van der Heijden, Inger Brandsma, Cristina Cruz, Dafni Chondronasiou, Marta Castroviejo-Bermejo, Ute Boon, Eva Schut, Eline van der Burg, Ellen Wientjens, Mark Pieterse, Christiaan Klijn, Sjoerd Klarenbeek, Fabricio Loayza-Puch, Ran Elkon, Liesbeth van Deemter, Sven Rottenberg, Marieke van de Ven, Dick H W Dekkers, Jeroen A A Demmers, Dik C van Gent, Reuven Agami, Judith Balmaña, Violeta Serra, Toshiyasu Taniguchi, Peter Bouwman, Jos Jonkers
Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to breast cancer. BRCA1 plays an important role in DNA double-strand break (DSB) repair via homologous recombination (HR), which is important for tumor suppression. Although BRCA1-deficient cells are highly sensitive to treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses to platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors in clinical trials...
August 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27443740/replication-fork-stability-confers-chemoresistance-in-brca-deficient-cells
#19
Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A Calvo, Nicholas J Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M Starnes, Julian R de Ruiter, Jeremy A Daniel, Panagiotis A Konstantinopoulos, David Cortez, Sharon B Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K Sharan, André Nussenzweig
Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks...
July 21, 2016: Nature
https://www.readbyqxmd.com/read/27411687/p120-catenin-is-critical-for-the-development-of-invasive-lobular-carcinoma-in-mice
#20
Milou Tenhagen, Sjoerd Klarenbeek, Tanya M Braumuller, Ilse Hofmann, Petra van der Groep, Natalie Ter Hoeve, Elsken van der Wall, Jos Jonkers, Patrick W B Derksen
Loss of E-cadherin expression is causal to the development of invasive lobular breast carcinoma (ILC). E-cadherin loss leads to dismantling of the adherens junction and subsequent translocation of p120-catenin (p120) to the cytosol and nucleus. Although p120 is critical for the metastatic potential of ILC through the regulation of Rock-dependent anoikis resistance, it remains unknown whether p120 also contributes to ILC development. Using genetically engineered mouse models with mammary gland-specific inactivation of E-cadherin, p120 and p53, we demonstrate that ILC formation induced by E-cadherin and p53 loss is severely impaired upon concomitant inactivation of p120...
December 2016: Journal of Mammary Gland Biology and Neoplasia
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