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      BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance

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          Abstract

          Carcinogenesis is a multistep process, and tumors frequently harbor multiple mutations regulating genome integrity, cell division and death. The integrity of cellular genome is closely controlled by the mechanisms of DNA damage signaling and DNA repair. The association of breast cancer susceptibility genes BRCA1 and BRCA2 with breast and ovarian cancer development was first demonstrated over 20 years ago. Since then the germline mutations within these genes were linked to genomic instability and increased risk of many other cancer types. Genomic instability is an engine of the oncogenic transformation of non-tumorigenic cells into tumor-initiating cells and further tumor evolution. In this review we discuss the biological functions of BRCA1 and BRCA2 genes and the role of BRCA mutations in tumor initiation, regulation of cancer stemness, therapy resistance and tumor progression.

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          Evolution of the cancer stem cell model.

          Antonija Kreso, John E. Dick (2014)
          Genetic analyses have shaped much of our understanding of cancer. However, it is becoming increasingly clear that cancer cells display features of normal tissue organization, where cancer stem cells (CSCs) can drive tumor growth. Although often considered as mutually exclusive models to describe tumor heterogeneity, we propose that the genetic and CSC models of cancer can be harmonized by considering the role of genetic diversity and nongenetic influences in contributing to tumor heterogeneity. We offer an approach to integrating CSCs and cancer genetic data that will guide the field in interpreting past observations and designing future studies. Copyright © 2014 Elsevier Inc. All rights reserved.
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            A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.

            Y Miki, J. Swensen, D Shattuck-Eidens … (1994)
            A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.
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              Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.

              Kathryn P Pennington, Tom Walsh, Maria I Harrell … (2014)
              Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain.
              Article 0 comments Cited 368 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cancer
                Journal ID (iso-abbrev): J Cancer
                Journal ID (publisher-id): jca
                Title: Journal of Cancer
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1837-9664
                Publication date Collection: 2019
                Publication date (Electronic): 14 May 2019
                Volume: 10
                Issue: 9
                Pages: 2109-2127
                Affiliations
                [1 ]OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;
                [2 ]Department of General and Medical Genetics, ESC "The Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv, Kyiv, Ukraine;
                [3 ]OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany; German Cancer Consortium (DKTK), Partner site Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
                Author notes
                ✉ Corresponding authors: Ielizaveta Gorodetska, email: Liza.Gorodetska@ 123456uniklinikum-dresden.de or Anna Dubrovska, email: Anna.Dubrovska@ 123456OncoRay.de

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                Publisher ID: jcav10p2109
                DOI: 10.7150/jca.30410
                PMC ID: 6548160
                PubMed ID: 31205572
                SO-VID: c20e7bfa-055f-466f-bc69-df559bb8ea14
                Copyright © © Ivyspring International Publisher
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                Date received : 4 October 2018
                Date accepted : 20 February 2019
                Categories
                Subject: Review

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: brca1,brca2,genomic instability,cancer stem cells,cancer treatment
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: brca1, brca2, genomic instability, cancer stem cells, cancer treatment

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