Mouse Models of BRCA1 and BRCA2 Deficiency

Total Page:16

File Type:pdf, Size:1020Kb

Mouse Models of BRCA1 and BRCA2 Deficiency Oncogene (2006) 25, 5885–5897 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc REVIEW Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects B Evers and J Jonkers Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Germline mutations in BRCA1 and BRCA2 are respon- risk of up to 80% for developing breast cancer and sible for a large proportion of hereditary breast and also display increased risk for ovarian cancer (B40% ovarian cancers. Soon after the identification of both for BRCA1 mutation carriers and B20% for BRCA2 genes in the mid-1990s, investigators set out to develop carriers, respectively) (Narod and Foulkes, 2004). In mouse models for the associated disease. Whereas most breast cancers arising in BRCA1/2 carriers, conventional Brca1 and Brca2 mouse mutants did not inactivation of the wild-type allele has occurred by reveal a strong phenotype in a heterozygous setting, means of loss of heterozygosity, thus abolishing normal most homozygous mutations caused embryonic lethality. protein expression (Smith et al., 1992; Collins et al., Consequently, development of mouse models for BRCA- 1995). BRCA1 tumors show a rather uniform tumor associated tumorigenesis required the generation of tissue- type of high-grade invasive ductal carcinomas, which are specific conditional knockout animals. In this review, we usually estrogen receptor (ER) and HER2/neu negative give an overview of the conventional and the conditional (Chappuis et al., 2000; Phillips, 2000). These properties mouse models of BRCA1 and BRCA2 deficiency gener- are reminiscent of ‘triple-negative’ (ER-, progesterone ated over the last decade, as well as the contribution receptor (PR)- and HER2/neu-negative) basal-like of these models to our understanding of the biological sporadic breast cancers (Livasy et al., 2006). Indeed, and molecular functions of BRCA1 and BRCA2. The cluster analysis of gene expression data from human most advanced mouse models for BRCA1- and BRCA2- breast cancers revealed strong similarity between associated tumorigenesis mimic human disease to the BRCA1-mutated tumors and basal-like breast cancers extent that they can be used in studies addressing (Sorlie et al., 2003). BRCA2 deficient tumors, on the clinically relevant questions. These models will help to other hand, show larger variety in histological classifica- resolve yet unanswered questions and to translate our tion and are not easily distinguished from the overall increasing knowledge of BRCA1 and BRCA2 biology into spectrum of sporadic tumors. While parity in the general clinical practice. population has been associated with decreased breast Oncogene (2006) 25, 5885–5897. doi:10.1038/sj.onc.1209871 cancer risk, parity per se was not found to influence risk in BRCA1 mutation carriers, although multiparity did Keywords: BRCA1; BRCA2; breast cancer; tumor seem to protect as well. For BRCA2, data suggest suppressor; mouse model that increasing parity is associated with increased risk of breast cancer. BRCA2-mutation carriers also have an increased risk of developing pregnancy-associated breast cancer (Cullinane et al., 2005). Introduction Breast cancer is the most common malignancy in Conventional Brca1 and Brca2 mutants women of the Western world, affecting up to 10% of the female population (Alberg and Helzlsouer, 1997). Following identification of the BRCA1 and BRCA2 An estimated 5% of all breast cancers is ascribed to breast cancer genes in humans, investigators sought hereditary predisposition. Intensive research in the early to recapitulate the effects of these genetic lesions 1990s has led to the identification of two major breast in mouse models. Several groups have generated a cancer susceptibility genes, BRCA1 (Futreal et al., 1994; range of conventional Brca1 and Brca2 knockout mice Miki et al., 1994) and BRCA2 (Wooster et al., 1995; with mutations in different portions of the genes (see Tavtigian et al., 1996). Individuals carrying mutations in Figures 1 and 2). Somewhat disappointingly, none of one allele of either BRCA1 or BRCA2 have a lifetime these mouse mutants showed a strong tumor predispos- ing phenotype in a heterozygous setting. When bred to homozygosity, most Brca1 and Brca2 mouse mutants Correspondence: Dr J Jonkers, Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, displayed severe embryonic lethal phenotypes. Although The Netherlands. these traits have hindered in vivo analysis of tumor E-mail: [email protected] suppressor functions of Brca1 and Brca2, conventional Mouse models of BRCA1/2 deficiency B Evers and J Jonkers 5886 Figure 1 Conventional and conditional Brca1 mutant alleles generated to date. Exon compositions for the predicted splice products are indicated, including the Brca1-D11 splice variant and the – for mice putative – Brca1-IRIS product. A w indicates that the predicted transcript contains a premature stop, resulting from a frame shift. In that case only the exons encoding the (predicted) truncated protein product are indicated. The bottom panel shows all BRCA1 splice variants known to exist in humans and mice. BRCA1 lacks exon 4, which had been erroneously identified during the initial cloning of the BRCA1 gene (Miki et al., 1994). EL: embryonic lethality day. mouse mutants have provided valuable insight into their observation that Brca-deficiency results in chromosomal biological roles. instability and increased sensitivity to DNA-damaging agents in cultured mouse cells (Sharan et al., 1997; Patel Functional clues et al., 1998; Shen et al., 1998; Tutt et al., 1999) and in Soon after the generation of Brca1 and Brca2 mouse living animals (Tutt et al., 2002). These phenotypes were mutants, it was acknowledged that the embryonic subsequently attributed to defects in repair of double- lethality of Brca1-deficient mice closely resembled the strand breaks (DSBs) by homologous recombination phenotype of mouse mutants of Rad51, a homologue (HR) (Moynahan et al., 1999, 2001; Xia et al., 2001). of the bacterial RecA protein known to be involved Whereas initial studies in Brca1 and Brca2 mouse in DNA damage repair (Lim and Hasty, 1996). mutants have highlighted similarities between both Subsequently, Rad51, Brca1 and Brca2 proteins were proteins, other research efforts have also revealed clear shown to have similar expression patterns during mouse differences (Venkitaraman, 2002). BRCA1 appears to embryogenesis (Lane et al., 1995; Marquis et al., 1995; be more of a signal integrator, linking together sensors Sharan et al., 1997; Blackshear et al., 1998) and during and response mechanisms of several types of DNA cell-cycle progression (Rajan et al., 1996; Chen et al., damage. In contrast, BRCA2 is thought to be more 1997). In addition, Brca1, Brca2 and Rad51 were found directly involved in homology-directed DSB repair, as it to co-localize in nuclear dot patterns (Scully et al., 1997; mediates the formation of a RAD51-DNA nucleopro- Chen et al., 1998) and to interact with each other tein filament that catalyzes strand invasion during HR (Scully et al., 1997; Sharan et al., 1997; Chen et al., (Pellegrini and Venkitaraman, 2004). 1998), suggesting a role for the BRCA proteins in For BRCA1, a wealth of data describes many DNA-damage repair. This notion was supported by the interactions with other proteins, as well as many Oncogene Mouse models of BRCA1/2 deficiency B Evers and J Jonkers 5887 Figure 2 Conventional and conditional Brca2 mutant alleles generated to date. The exon composition of the predicted splice product from the mutant allele is indicated. A w indicates that the predicted transcript contains a premature stop, resulting from a frame shift. In that case only the exons encoding the (predicted) truncated protein product are indicated. BRCrepeats that are still encoded by the predicted transcript are indicated. EL: embryonic lethality day. functions besides the involvement in the maintenance of defect (Hakem et al., 1996; Liu et al., 1996; Ludwig et al., genetic stability. Thus, apart from DNA repair, func- 1997; Suzuki et al., 1997). This striking observation tions have been described for BRCA1 in all phases of introduced a paradox in the biology of BRCA1 and the cell cycle (Deng, 2006), transcription (Lane, 2004) BRCA2. Whereas BRCA-deficient tumor cells proliferate and DNA decatenation (Lou et al., 2005). Studies with the rapidly in situ, cells in developing Brca-deficient embryos Brca1 mouse mutants – or primary cells derived thereof – suffer from a proliferation defect. Although this paradox have revealed several distinct activities of Brca1, including is still unresolved, part of it might be explained by its potential roles in the G2–M cell cycle and spindle the genetic interactions between BRCA1/2 and the p53 assembly checkpoints (Xu et al., 1999b; Wang et al., pathway. Growth-arrested Brca1- and Brca2-deficient 2004a), maintenance of telomere integrity (McPherson embryos showed activation of the Cdkn1a gene encoding et al., 2006) and transcriptional repression of unsynapsed the cyclin-dependent kinase (cdk) inhibitor p21, a p53 chromosomal regions during meiosis (Turner et al., 2004). downstream target known to function in the G1–S cell Interesting with respect to the gender specificity observed cycle checkpoint (Hakem et al., 1996; Suzuki et al., 1997). in BRCA-associated cancers is the reported role for To investigate the role of p53 and p21 in Brca-associated BRCA1 in
Recommended publications
  • FAQ505 -- BRCA1 and BRCA2 Mutations
    AQ FREQUENTLY ASKED QUESTIONS FAQ505 fWOMEN’S HEALTH BRCA1 and BRCA2 Mutations • What is cancer? • What causes cancer? • What is hereditary breast and ovarian cancer syndrome? • What are BRCA1 and BRCA2? • How much do BRCA mutations increase the risk of breast cancer? • How much do BRCA mutations increase the risk of ovarian cancer? • Do BRCA mutations increase the risk of other types of cancer? • How common are BRCA mutations? • Should I be tested for BRCA mutations? • What is genetic counseling? • Why don’t doctors test everyone for BRCA mutations? • How is testing for BRCA mutations done? • What does a negative test result mean? • What does an unclear test result mean? • What does a positive test result mean? • How can you prevent cancer if you test positive for a BRCA mutation? • What breast cancer screening tests are available? • What ovarian screening tests are available? • What medication can help prevent breast cancer? • What medications can help prevent ovarian cancer? • Can surgery help prevent breast cancer? • What are the side effects of a mastectomy? • Can surgery help prevent ovarian cancer? • What are the side effects of removing the ovaries? • What else should I think about before choosing risk-reducing surgery? • I am concerned about discrimination based on genetic testing results. What should I know? • What should I know about direct-to-consumer genetic tests? • Glossary What is cancer? Normal cells in the body grow, divide, and are replaced on a routine basis. Sometimes, cells divide abnormally and begin to grow out of control. These cells may form growths or tumors.Tumors can be benign (not cancer) or malignant (cancer).
    [Show full text]
  • BRCA1 and BRCA2 Play an Activities Have No Relevant Financial Relationships to Important Role in the Repair of Damaged DNA and the Disclose
    Alaska Pharmacists Association Continuing Education Home Study Series Program 0139-0000-19-201-H04-P/T Genetic Mutations in Quarterly AKPhA Newsletter Cancer: BRCA1 and Release Date 10/07/2019 Expiration Date 10/07/2022 BRCA2 CPE Hours: 2.0 (0.2 CEU) Authors: This lesson is a knowledge-based CPE activity Danielle Hess, PharmD Candidate 2020 and is targeted to pharmacists and technicians Anne Marie Bott, PharmD, BCOP, BCPS, in all practice settings. NCPS, Alaska Native Medical Center Learning Objectives Cancer is a genetic disease that results from an At the completion of this activity, the participant accumulation of mutations in genes that normally will be able to: control cellular growth. This accumulation of mutations 1. State two positive changes you can make to can arise from either somatic or germinal tissue. While your practice following participation in this the majority of mutations are somatic and result from series. environmental exposures, lifestyle, the aging process, or simply chance, germline mutations are inherited. These 2. Summarize three practice updates or changes inherited mutations in specific tumor suppressor genes you acquired while participating in this series. and DNA mismatch genes predispose individuals to 1 Disclosure various hereditary cancer syndromes. The author(s) and other individuals responsible for Of the tumor suppressor genes associated with inherited planning AKPhA continuing pharmacy education cancer syndromes, BRCA1 and BRCA2 play an activities have no relevant financial relationships to important role in the repair of damaged DNA and the disclose. stability of genetic material within cells. However, when these genes are mutated or altered, the DNA repair Fees process may not function properly, which causes cells to CE processing is free for AKPhA members.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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).
    [Show full text]
  • (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.
    [Show full text]
  • The Ethical Implications of Emerging Genetic Predictors of Poor Organ Transplant Outcomes
    THE ETHICAL IMPLICATIONS OF EMERGING GENETIC PREDICTORS OF POOR ORGAN TRANSPLANT OUTCOMES by Michael Aloysius Freeman Bachelor of Arts, Siena College, 2004 Doctor of Medicine, Albany Medical College, 2008 Submitted to the Graduate Faculty of the Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Master of Arts University of Pittsburgh 2016 UNIVERSITY OF PITTSBURGH DIETRICH SCHOOL OF ARTS AND SCIENCES This thesis was presented by Michael A Freeman It was defended on July 20th, 2016 and approved by Lisa S. Parker, Professor, Department of Human Genetics, University of Pittsburgh Mark R. Wicclair, Professor, Department of Philosophy, West Virginia University Benjamin E. Hippen, Associate Clinical Professor, Department of Medicine University of North Carolina at Chapel Hill Thesis Director: Lisa S. Parker, Professor, Department of Human Genetics ii Copyright © by Michael A Freeman 2016 iii THE ETHICAL IMPLICATIONS OF EMERGING GENETIC PREDICTORS OF POOR ORGAN TRANSPLANT OUTCOMES Michael A Freeman, MA, MD University of Pittsburgh, 2016 Abstract: Emerging research is beginning to identify genetic risk factors which may predict an increased likelihood of rejection following transplantation. The identification of these predictors prompt us to consider how we should incorporate this information into the process of transplant candidate evaluation and organ allocation, as well as the ethical implications of such incorporation. In order to ground this analysis, this thesis begins with an examination of how we consider other predictors of poor transplant outcomes currently, as interpreted in concordance with the US transplant system’s dual goals of efficacious and just organ allocation. It then proceeds with a brief summary of the current research on genetic predictors of poor transplant outcome, followed by a specific examination of the mechanisms by which these genes are investigated.
    [Show full text]
  • 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.
    [Show full text]
  • 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).
    [Show full text]
  • Molecular Profiles of BRCA1-Mutated and Matched Sporadic Breast Tumours: Relation with Clinico-Pathological Features
    British Journal of Cancer (2001) 85(4), 538–545 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.1937, available online at http://www.idealibrary.com on IIH ii http://www.bjcancer.com Molecular profiles of BRCA1-mutated and matched sporadic breast tumours: relation with clinico-pathological features EMJJ Berns1, IL van Staveren1, L Verhoog1,2, AMW van de Ouweland3, M Meijer-van Gelder1, H Meijers-Heijboer3, H Portengen1, JA Foekens1, LCJ Dorssers2 and JGM Klijn1 1Division of Endocrine Oncology, Department of Medical Oncology, Rotterdam Cancer Center (Daniel den Hoed Kliniek) and University Hospital Rotterdam; 2Department of Pathology and 3Department of Clinical Genetics, Erasmus University Rotterdam, The Netherlands Summary About 5–10% of breast cancers are hereditary; a genetically and clinically heterogeneous disease in which several susceptibility genes, including BRCA1, have been identified. While distinct tumour features can be used to estimate the likelihood that a breast tumour is caused by a BRCA1 germline mutation it is not yet possible to categorize a BRCA1 mutated tumour. The aim of the present study is to molecularly classify BRCA1 mutated breast cancers by resolving gene expression patterns of BRCA1 and matched sporadic surgical breast tumour specimens. The expression profiles of 6 frozen breast tumour tissues with a proven BRCA1 gene mutation were weighed against those from 12 patients without a known family history but who had similar clinico-pathological characteristics. In addition two fibroblast cultures, the breast cancer cell-line HCC1937 and its corresponding B-lymphoblastoid cell line (heterozygous for mutation BRCA1 5382insC) and an epithelial ovarian cancer cell line (A2780) were studied.
    [Show full text]
  • 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.
    [Show full text]
  • 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].
    [Show full text]