Determination of Molecular Markers for BRCA1 and BRCA2 Heterozygosity Using Gene Expression Profiling
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Brca2 Is Required for Embryonic Cellular Proliferation in the Mouse
Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Brca2 is required for embryonic cellular proliferation in the mouse Akira Suzuki, 1'2'6 Jos6 Luis de la Pompa, 1'2'6 RazqaUah Hakem, 1'2 Andrew Elia, 1'2 Ritsuko Yoshida, 1'2 Rong Mo, 3'4 Hiroshi Nishina, 1'2 Tony Chuang, 1'2 Andrew Wakeham, ~'2 Annick Itie, ~'2 Wilson Koo, ~'2 Phyllis Billia, ~'2 Alexandra Ho, 1'2 Manabu Fukumoto, 5 Chi Chung Hui, 3'4 and Tak W. Mak 1'2"7 1Amgen Institute, Toronto, Ontario, Canada M5G 2C1; 2Ontario Cancer Institute, Department of Medical Biophysics and Immunology, 3Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada; 4program in Developmental Biology and Division of Endocrinology Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8; SDepartment of Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 606 Mutations of the tumor suppressor gene BRCA2 are associated with predisposition to breast and other cancers. Homozygous mutant mice in which exons 10 and 11 of the Brca2 gene were deleted by gene targeting (Brca2 I°-11) die before day 9.5 of embryogenesis. Mutant phenotypes range from severely developmentally retarded embryos that do not gastrulate to embryos with reduced size that make mesoderm and survive until 8.5 days of development. Although apoptosis is normal, cellular proliferation is impaired in Brca2 ~°-H mutants, both in vivo and in vitro. In addition, the expression of the cyclin-dependent kinase inhibitor p21 is increased. Thus, Brca2 l°-H mutants are similar in phenotype to Brcal 5-6 mutants but less severely affected. -
Nedd4 and Nedd4-2: Closely Related Ubiquitin-Protein Ligases with Distinct Physiological Functions
Cell Death and Differentiation (2010) 17, 68–77 & 2010 Macmillan Publishers Limited All rights reserved 1350-9047/10 $32.00 www.nature.com/cdd Review Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions B Yang*,1 and S Kumar*,2 The Nedd4 (neural precursor cell-expressed developmentally downregulated gene 4) family of ubiquitin ligases (E3s) is characterized by a distinct modular domain architecture, with each member consisting of a C2 domain, 2–4 WW domains, and a HECT-type ligase domain. Of the nine mammalian members of this family, Nedd4 and its close relative, Nedd4-2, represent the ancestral ligases with strong similarity to the yeast, Rsp5. In Saccharomyces cerevisiae Rsp5 has a key role in regulating the trafficking, sorting, and degradation of a large number of proteins in multiple cellular compartments. However, in mammals the Nedd4 family members, including Nedd4 and Nedd4-2, appear to have distinct functions, thereby suggesting that these E3s target specific proteins for ubiquitylation. In this article we focus on the biology and emerging functions of Nedd4 and Nedd4-2, and review recent in vivo studies on these E3s. Cell Death and Differentiation (2010) 17, 68–77; doi:10.1038/cdd.2009.84; published online 26 June 2009 Ubiquitylation controls biological signaling in many different ubiquitin-protein ligase (E3). A protein can be monoubiquity- ways.1,2 For example, the ubiquitylation of a misfolded or lated, multi-monoubiquitylated, or polyubiquitylated, and the damaged protein leads to its degradation by the 26S type of ubiquitylation determines the fate of the protein.1,2 proteasome before it can get to its subcellular site where it Ubiquitin itself contains seven lysine residues, all of which can normally functions. -
BRCA1 and BRCA2 Full Gene Sequence Analysis and Common Deletion/Duplication Variants
BRCA1 and BRCA2 Full Gene Sequence Analysis and Common Deletion/Duplication Variants Testing includes full gene sequencing of exons and 25 base pairs of introns of BRCA 1 and 2 and the common deletions of BRCA1 (exon 13 del 3.835kb, exon 13 dup 6kb, exon 14-20 del 26kb, exon 22 del 510bp, exon 8-9 del 7.1kb). Sequencing does not include the promoter, enhancers or splicing modulators in intronic regions. Deletion duplication analysis is limited to the commonly reported variants; refer to full deletion/duplication testing. Indication: This testing is indicated for individuals that meet the criteria for Hereditary Breast and Ovarian Cancer listed in the National Comprehensive Cancer Network (NCCN) guidelines. For assistance with interpreting guidelines, please contact Henry Ford Precision Genomic Diagnostics, or refer to genetic counseling for evaluation. Testing on minors is not indicated. BRCA1 and BRCA2 are genes that code for proteins that help repair DNA damage. Inherited mutations in BRCA 1 or 2, in combination with additional acquired mutations, can result in increased risk for developing cancer. Specific mutations in BRCA1 and BRCA2 increase the risk of breast and ovarian cancers, and have been associated with increased risk of several additional types of cancer. BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. In addition, BRCA1 and BRCA2 account for about 15 percent of ovarian cancers overall. Breast and ovarian cancers associated with BRCA1 and BRCA2 mutations tend to develop at younger ages than their nonhereditary counterparts. -
Infrequency of BRCA2 Alterations in Head and Neck Squamous Cell Carcinoma
Oncogene (1997) 14, 2189 ± 2193 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 Infrequency of BRCA2 alterations in head and neck squamous cell carcinoma Haskell Kirkpatrick1, Pamela Waber1, To Hoa-Thai1, Robert Barnes1, Sherri Osborne-Lawrence1, John Truelson2, Perry Nisen1 and Anne Bowcock1 1Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-8591; 2Department of Otolaryngology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-8591, USA Alterations of BRCA2 result in increased susceptibility chromosome regions 1p, 3p, 7q, 9p, 11q and 17p to breast cancer in both men and women (relative (Cowan et al., 1992; Jin et al., 1993; Maestro et al., lifetime risks of 0.06 and 0.8 respectively). BRCA2 maps 1993; Rowley et al., 1996; Wu et al., 1994; van der Riet to 13q12-q13 and encodes a transcript of 10 157 bp. et al., 1994; Reed et al., 1996; Nawroz et al., 1994). Other cancers that have been described in BRCA2 Loss of heterozygosity (LOH) studies that frequently mutation carriers include those of the larynx. Human reveal the locale of tumor suppressor genes (Ponder, chromosome 13q has been shown previously by LOH 1988) have been performed by us and others and studies to harbor several tumor suppressor genes for head revealed regions on chromosomes 3, 8, 9, 13, 17p12 and neck squamous cell carcinoma (HNSCCs). We and multiple others (Nawroz et al., 1994; Ah-See et al., therefore examined the role of BRCA2 in the develop- 1994; Li et al., 1994). -
(NF1) Defects Are Common in Human Ovarian Serous Carcinomas and Co-Occur with TP53 Mutations
Volume 10 Number 12 December 2008 pp. 1362–1372 1362 www.neoplasia.com Neurofibromin 1 (NF1) Defects Navneet Sangha*, Rong Wu*, Rork Kuick†, Scott Powers‡, David Mu§, Diane Fiander*, Are Common in Human Ovarian Kit Yuen*, Hidetaka Katabuchi¶, Hironori Tashiro¶, Serous Carcinomas and Co-occur Eric R. Fearon*,†,# and Kathleen R. Cho*,†,# 1,2 with TP53 Mutations *Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA; †The Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, MI 48109, USA; ‡Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; §Department of Pathology, Penn State University College of Medicine, Hershey, PA 17033, USA; ¶Department of Gynecology, Kumamoto University, Kumamoto, 860-8556, Japan; #Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109, USA Abstract Ovarian serous carcinoma (OSC) is the most common and lethal histologic type of ovarian epithelial malignancy. Mutations of TP53 and dysfunction of the Brca1 and/or Brca2 tumor-suppressor proteins have been implicated in the molecular pathogenesis of a large fraction of OSCs, but frequent somatic mutations in other well-established tumor-suppressor genes have not been identified. Using a genome-wide screen of DNA copy number alterations in 36 primary OSCs, we identified two tumors with apparent homozygous deletions of the NF1 gene. Subsequently, 18 ovarian carcinoma–derived cell lines and 41 primary OSCs were evaluated for NF1 alterations. Markedly re- duced or absent expression of Nf1 protein was observed in 6 of the 18 cell lines, and using the protein truncation test and sequencing of cDNA and genomic DNA, NF1 mutations resulting in deletion of exons and/or aberrant splicing of NF1 transcripts were detected in 5 of the 6 cell lines with loss of NF1 expression. -
Inherited Cancer Predisposition Syndromes in Greece
ANTICANCER RESEARCH 28: 1341-1348 (2008) Review Inherited Cancer Predisposition Syndromes in Greece ANGELA APESSOS1, EIRINI PAPADOPOULOU1, IOULIA BELOGIANNI1, SOTIRIS BARATSIS2, JOHN K. TRIANTAFILLIDIS3, PARIS KOSMIDIS3, EIRINI KARYDAS4, EVANGELOS BRIASOULIS5, CHRISTOS PISIOTIS6, KOSTAS PAPAZISIS7 and GEORGE NASIOULAS1,3 1Department of Molecular Biology, 4Breast Cancer Center, 6DTCA HYGEIA SA, Kifissias Av. & 4 Er. Stavrou str, 151 23 Maroussi, Athens; 2First Surgical Department, ‘Evangelismos' General Hospital of Athens, 45-47 Ipsilantou Street, Kolonaki, Athens; 3Hellenic Cooperative Oncology Group; 5Department of Medical Oncology, University Hospital of Ioannina, Medical School, University of Ioannina, Ioannina; 7“Theagenion” Cancer Hospital, Al. Simeonides str. 2, 54007 Thessaloniki, Greece Abstract. Hereditary cancer syndromes comprise Hereditary cancer syndromes comprise approximately 5-10% approximately 5-10% of diagnosed carcinomas. They are of diagnosed carcinomas. They are caused by mutations in caused by mutations in specific genes. Carriers of mutations in specific genes. Carriers of such mutations are at an increased these genes are at an increased risk of developing cancer at a risk of developing cancer at an early age. Today, there are a young age. When there is a suspicion of a hereditary cancer number of options available for the prevention and treatment predisposition syndrome a detailed family tree of the patient of inherited cancer predisposition syndrome for patients and requesting screening is constructed. DNA is isolated from all their families. Furthermore, advances in molecular biology available members of the family. Mutation detection is carried and in vitro fertilization techniques have made possible out on DNA from an affected family member. If a mutation is preimplantation genetic diagnosis (PGD) for the prevention found the remaining family is screened. -
E3 Ubiquitin Ligases: Key Regulators of Tgfβ Signaling in Cancer Progression
International Journal of Molecular Sciences Review E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression Abhishek Sinha , Prasanna Vasudevan Iyengar and Peter ten Dijke * Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; [email protected] (A.S.); [email protected] (P.V.I.) * Correspondence: [email protected]; Tel.: +31-71-526-9271 Abstract: Transforming growth factor β (TGFβ) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGFβ signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGFβ is dependent on cellular context, and TGFβ can perform both anti- and pro-oncogenic roles. TGFβ acts by binding to specific cell surface TGFβ type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGFβ signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGFβ receptor and intracellular signaling components. -
Lessons Learned from BRCA1 and BRCA2
Oncogene (2000) 19, 6159 ± 6175 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Lessons learned from BRCA1 and BRCA2 Lei Zheng1, Shang Li1, Thomas G Boyer1 and Wen-Hwa Lee*,1 1Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, Texas, TX 78245, USA BRCA1 and BRCA2 are breast cancer susceptibility susceptibility genes has provided two human genetic genes. Mutations within BRCA1 and BRCA1 are models for studies of breast cancer. responsible for most familial breast cancer cases. To understand how the loss of BRCA1 or BRCA2 Targeted deletion of Brca1 or Brca2 in mice has function leads to breast cancer formation, mouse revealed an essential function for their encoded products, genetic models for BRCA1 or BRCA2 mutations have BRCA1 and BRCA2, in cell proliferation during been established. This work has revealed that Brca1 embryogenesis. Mouse models established from condi- homozygous deletions are lethal at early embryonic tional expression of mutant Brca1 alleles develop days (E)5.5 ± 13.5 (Gowen et al., 1996; Hakem et al., mammary gland tumors, providing compelling evidence 1996; Liu et al., 1996; Ludwig et al., 1997). Three that BRCA1 functions as a breast cancer suppressor. independent groups generated distinct mutations within Human cancer cells and mouse cells de®cient in BRCA1 Brca1, yet nonetheless observed similar embryonic or BRCA2 exhibit radiation hypersensitivity and phenotypes, including defects in both gastrulation and chromosomal abnormalities, thus revealing a potential cellular proliferation, and death at E6.5 (Hakem et al., role for both BRCA1 and BRCA2 in the maintenance of 1996; Liu et al., 1996; Ludwig et al., 1997). -
Smurf2-Mediated Stabilization of DNA Topoisomerase Iiα Controls Genomic Integrity
Published OnlineFirst June 13, 2017; DOI: 10.1158/0008-5472.CAN-16-2828 Cancer Molecular and Cellular Pathobiology Research Smurf2-Mediated Stabilization of DNA Topoisomerase IIa Controls Genomic Integrity Andrea Emanuelli1, Aurora P. Borroni1, Liat Apel-Sarid2, Pooja A. Shah1, Dhanoop Manikoth Ayyathan1, Praveen Koganti1, Gal Levy-Cohen1, and Michael Blank1 Abstract DNA topoisomerase IIa (Topo IIa) ensures genomic integ- pathological chromatin bridges formed during mitosis, a trait rity and unaltered chromosome inheritance and serves as a of Topo IIa–deficient cells and a hallmark of chromosome major target of several anticancer drugs. Topo IIa function is instability. Introducing Topo IIa into Smurf2-depleted cells well understood, but how its expression is regulated remains rescued this phenomenon. Smurf2 was a determinant of Topo unclear. Here, we identify the E3 ubiquitin ligase Smurf2 as a IIa protein levels in normal and cancer cells and tissues, and its physiologic regulator of Topo IIa levels. Smurf2 physically levels affected cell sensitivity to the Topo II–targeting drug interacted with Topo IIa and modified its ubiquitination status etoposide. Our results identified Smurf2 as an essential regu- to protect Topo IIa from the proteasomal degradation in dose- lator of Topo IIa, providing novel insights into its control and catalytically dependent manners. Smurf2-depleted cells and into the suggested tumor-suppressor functions of Smurf2. exhibited a reduced ability to resolve DNA catenanes and Cancer Res; 77(16); 1–11. Ó2017 AACR. Introduction mice knockout for Smurf2 develop a wide spectrum of tumors in different organs and tissues. These and other studies estab- DNA topoisomerase IIa (Topo IIa) is the major form of the lished Smurf2 as an important regulator of genomic integrity, Topo II enzyme in cycling vertebrate cells that acts to untangle whose inactivation results in carcinogenesis (7). -
The UBE2L3 Ubiquitin Conjugating Enzyme: Interplay with Inflammasome Signalling and Bacterial Ubiquitin Ligases
The UBE2L3 ubiquitin conjugating enzyme: interplay with inflammasome signalling and bacterial ubiquitin ligases Matthew James George Eldridge 2018 Imperial College London Department of Medicine Submitted to Imperial College London for the degree of Doctor of Philosophy 1 Abstract Inflammasome-controlled immune responses such as IL-1β release and pyroptosis play key roles in antimicrobial immunity and are heavily implicated in multiple hereditary autoimmune diseases. Despite extensive knowledge of the mechanisms regulating inflammasome activation, many downstream responses remain poorly understood or uncharacterised. The cysteine protease caspase-1 is the executor of inflammasome responses, therefore identifying and characterising its substrates is vital for better understanding of inflammasome-mediated effector mechanisms. Using unbiased proteomics, the Shenoy grouped identified the ubiquitin conjugating enzyme UBE2L3 as a target of caspase-1. In this work, I have confirmed UBE2L3 as an indirect target of caspase-1 and characterised its role in inflammasomes-mediated immune responses. I show that UBE2L3 functions in the negative regulation of cellular pro-IL-1 via the ubiquitin- proteasome system. Following inflammatory stimuli, UBE2L3 assists in the ubiquitylation and degradation of newly produced pro-IL-1. However, in response to caspase-1 activation, UBE2L3 is itself targeted for degradation by the proteasome in a caspase-1-dependent manner, thereby liberating an additional pool of IL-1 which may be processed and released. UBE2L3 therefore acts a molecular rheostat, conferring caspase-1 an additional level of control over this potent cytokine, ensuring that it is efficiently secreted only in appropriate circumstances. These findings on UBE2L3 have implications for IL-1- driven pathology in hereditary fever syndromes, and autoinflammatory conditions associated with UBE2L3 polymorphisms. -
Identification of Novel BRCA2-Binding Proteins That Are Essential for Meiotic Homologous Recombination
Identification of novel BRCA2-binding proteins that are essential for meiotic homologous recombination Jingjing Zhang Department of Chemistry and Molecular Biology University of Gothenburg 2021 Identification of novel BRCA2-binding proteins that are essential for meiotic homologous recombination © Author 2021 [email protected] ISBN 978-91-8009-166-4 (PRINT) ISBN 978-91-8009-167-1 (PDF) http://hdl.handle.net/2077/67213 Printed in Gothenburg, Sweden 2021 Printed by STEMA SPECIALTRYCK AB For CD village Identification of novel BRCA2-binding proteins that are essential for meiotic homologous recombination Jingjing Zhang Department of Chemistry and Molecular Biology, University of Gothenburg, SE-40530 Gothenburg, Sweden Abstract Meiotic recombination is a molecular process in which the induction and repair of programmed DNA double-strand breaks (DSBs) creates genetic exchange between homologous chromosomes and thus increases genetic diversity and ensures chromosome segregation. Breast cancer susceptibility gene 2 (BRCA2) is a potent cancer suppressor and is required for DSB repair by homologous recombination (HR) in mitosis. However, due to the embryonic lethality of the Brca2 knockout (KO) mice, the role of BRCA2 in meiotic HR is less well defined. In our work, we have identified two novel meiosis-specific proteins, MEILB2 (meiotic localizer of BRCA2) and BRME1 (BRCA2 and MEILB2-associating protein 1) that form a ternary complex with BRCA2 and shed light on BRCA2 and its co-factors' roles during meiotic HR. In Meilb2 KO male mice, the localization of the recombinases RAD51 and DMC1, which catalyze the homology-directed repair of DSBs, is almost totally abolished, leading to errors in meiotic DSB repair and subsequent sterility. -
BRCA in Gastrointestinal Cancers: Current Treatments and Future Perspectives
cancers Review BRCA in Gastrointestinal Cancers: Current Treatments and Future Perspectives Eleonora Molinaro, Kalliopi Andrikou, Andrea Casadei-Gardini * and Giulia Rovesti Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy; [email protected] (E.M.); [email protected] (K.A.); [email protected] (G.R.) * Correspondence: [email protected] Received: 10 October 2020; Accepted: 11 November 2020; Published: 12 November 2020 Simple Summary: BRCA gene mutations are progressively gaining more attention in the context of gastrointestinal malignancies, especially in pancreatic cancer where their identification can have both therapeutic and surveillance relevance. Abstract: A strong association between pancreatic cancer and BRCA1 and BRCA2 mutations is documented. Based on promising results of breast and ovarian cancers, several clinical trials with poly (ADP-ribose) polymerase inhibitors (PARPi) are ongoing for gastrointestinal (GI) malignancies, especially for pancreatic cancer. Indeed, the POLO trial results provide promising and awaited changes for the pancreatic cancer therapeutic landscape. Contrariwise, for other gastrointestinal tumors, the rationale is currently only alleged. The role of BRCA mutation in gastrointestinal cancers is the subject of this review. In particular, we aim to provide the latest updates about novel therapeutic strategies that, exploiting DNA repair defects, promise to shape the future therapeutic scenario of GI cancers. Keywords: BRCA1; BRCA2; gastrointestinal cancers; HRD; pancreatic cancer; Olaparib; PARP inhibitors; surveillance 1. Introduction BRCA1 and BRCA2 are famous tumor susceptibility genes. They encode for proteins playing a crucial role in the correct repair of damaged DNA. Indeed, these genes are key components of the homologous recombination (HR) pathway [1].