Skip to main content

Advertisement

SpringerLink
Log in

A comprehensive analysis of BRCA2 gene: focus on mechanistic aspects of its functions, spectrum of deleterious mutations, and therapeutic strategies targeting BRCA2-deficient tumors

  • Review Article
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

BRCA2is the main susceptibility gene known to be involved in the pathogenesis of breast cancer. It plays an important role in maintaining the genome stability by homologous recombination through DNA double-strand breaks repairing, by interacting with various other proteins including RAD51, DSS1, RPA, MRE11, PALB2, and p53. BRCA2-deficient cells show the abnormalities of chromosome number. BRCA2 is also found to be involved in centrosome duplication specifically in the metaphase to anaphase transition. Inactivation or depletion of BRCA2 leads to centrosome amplification that results in unequal separation of chromosomes. BRCA2 localizes with central spindle and midbody during telophase and cytokinesis. Inactivation or depletion of BRCA2 leads to multinucleation of cell. Around 2000 mutations have been reported in BRCA2 gene. BRCA2-deficient tumors are being taking into consideration for targeted cancer therapy by using different inhibitors like poly ADP-ribose polymerase and thymidylate synthase. The present review focusses on the role of BRCA2 in various critical cellular processes based on the mechanistic approaches. Mutations reported in the BRCA2 gene in various ethnic groups till date have also been compiled with an insight into the functional aspects of these alterations. The therapeutic strategies for targeting BRCA2-deficient tumors have also been targeted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

BRCA1:

Breast cancer type 1

BRCA2:

Breast cancer type 2

RPA:

Replication protein A

MRE11:

Meiotic recombination 11

PALB2:

Partner and localizer of BRCA2

SSB:

Single-strand binding protein

HR:

Homologous recombination

DDR:

DNA damage response

ATR:

Ataxia telangiectasia and Rsd3-related

ATM:

Ataxia telangiectasia mutated

EMSY:

BRCA2 interacting transcriptional repressor

AURKA:

Serine/threonine kinase Aurora-A

UCV:

Unknown classified variants

LOH:

Loss of heterozygosity

NLS:

Nuclear localization signal

DBD:

Double-strand break domain

TS:

Thymidylate synthase

PARP:

Poly ADP-ribose polymerase

FU:

Fluoropyrimidines

References

  1. Lo PK, Wolfson B, Zhou X, Duru N, Gernapudi R, Zhou Q. Noncoding RNAs in breast cancer. Brief Funct Genom. 2016;15(3):200–21.

    Article  Google Scholar 

  2. Wasson MK, Chauhan PS, Singh LC, Katara D, Sharma JD, Zomawia E, Kataki A, Kapur S, Saxena S. Association of DNA repair and cell cycle gene variations with breast cancer risk in Northeast Indian population: a multiple interaction analysis. Tumor Biol. 2014;35(6):5885–94.

    Article  CAS  Google Scholar 

  3. Shiovitz S, Korde LA. Genetics of breast cancer: a topic in evolution. Ann Oncol. 2015;26(7):1291–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Huang Z, Wen W, Zheng Y, Gao YT, Wu C, Bao P, Zhang M. Breast cancer incidence and mortality: trends over 40 years among women in Shanghai, China. Ann Oncol. 2016;27(6):1129–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Spugnesi L, Balia C, Collavoli A, Falaschi E, Quercioli V, Caligo MA, Galli A. Effect of the expression of BRCA2 on spontaneous homologous recombination and DNA damage-induced nuclear foci in Saccharomyces cerevisiae. Mutagenenesis. 2013;28:187–95.

    Article  CAS  Google Scholar 

  6. Venkitaraman AR. Chromosome stability, DNA recombination and the BRCA2 tumour suppressor. Curr Opin Cell Biol. 2001;13(3):338–43.

    Article  CAS  PubMed  Google Scholar 

  7. Gochhait S, Bukhari SIA, Bairwa N, Vadhera S, Darvishi K, Raish M, Bamezai RN. Implication of BRCA2-26G>A 5′ untranslated region polymorphism in susceptibility to sporadic breast cancer and its modulation by p53 codon 72 Arg> Pro polymorphism. Breast Cancer Res. 2007;9(5):1.

    Article  Google Scholar 

  8. Rudkin TM, Foulkes WD. BRCA2: breaks, mistakes and failed separations. Trends Mol Med. 2005;11(4):145–8.

    Article  CAS  PubMed  Google Scholar 

  9. Schlacher K, Christ N, Siaud N, Egashira A, Wu H, Jasin M. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell. 2011;145(4):529–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jonsdottir AB, Vreeswijk MP, Wolterbeek R, Devilee P, Tanke HJ, Eyfjörd JE, Szuhai K. BRCA2 heterozygosity delays cytokinesis in primary human fibroblasts. Anal Cell Pathol. 2009;31(3):191–201.

    CAS  Google Scholar 

  11. Zhao W, Vaithiyalingam S, San Filippo J, Maranon DG, Jimenez-Sainz J, Fontenay GV, Chazin WJ. Promotion of BRCA2-dependent homologous recombination by DSS1 via RPA targeting and DNA mimicry. Mol Cell. 2015;59(2):176–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang F, Shi J, Bian C, Yu X. Poly (ADP-Ribose) mediates the BRCA2-dependent early DNA damage response. Cell Rep. 2015;13(4):678–89.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhang F, Ma J, Wu J, Ye L, Cai H, Xia B, Yu X. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol. 2009;19(6):524–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Buisson R, Niraj J, Pauty J, Maity R, Zhao W, Coulombe Y, Masson JY. Breast cancer proteins PALB2 and BRCA2 stimulate polymerase η in recombination-associated DNA synthesis at blocked replication forks. Cell Rep. 2014;6(3):553–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Krejčí L, Altmannová V, Špírek M, Zhao X, Krejci L, Altmannova V, Spirek M, Zhao X. Homologous recombination and its regulation. Nucleic Acids Res. 2012;40(13):5795–818.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Verma S, Rao BJ. p53 suppresses BRCA2-stimulated ATPase and strand exchange functions of human RAD51. J Biochem. 2013;154(3):237–48.

    Article  CAS  PubMed  Google Scholar 

  17. O’Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015;60(4):547–60.

    Article  PubMed  Google Scholar 

  18. Song L, Dai T, Xie Y, Wang C, Lin C, Wu Z, Li J. Up-regulation of miR-1245 by c-myc targets BRCA2 and impairs DNA repair. J Mol Cell Biol. 2012;4(2):108–17.

    Article  CAS  PubMed  Google Scholar 

  19. Haber DA. The BRCA2-EMSY connection: implications for breast and ovarian tumorigenesis. Cell. 2003;115(5):507–8.

    Article  CAS  PubMed  Google Scholar 

  20. Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Livingston DM. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22(6):719–29.

    Article  CAS  PubMed  Google Scholar 

  21. Lekomtsev S, Guizetti J, Pozniakovsky A, Gerlich DW, Petronczki M. Evidence that the tumor-suppressor protein BRCA2 does not regulate cytokinesis in human cells. J Cell Sci. 2010;123(9):1395–400.

    Article  CAS  PubMed  Google Scholar 

  22. Mondal G, Rowley M, Guidugli L, Wu J, Pankratz VS, Couch FJ. BRCA2 localization to the midbody by filamin A regulates cep55 signaling and completion of cytokinesis. Dev Cell. 2012;23(1):137–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Daniels MJ, Wang Y, Lee M, Venkitaraman AR. Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science. 2004;306(5697):876–9.

    Article  CAS  PubMed  Google Scholar 

  24. Gudmundsdottir K, Ashworth A. BRCA2 in meiosis: turning over a new leaf. Trends Cell Biol. 2004;14(8):401–4.

    Article  CAS  PubMed  Google Scholar 

  25. Lee M, Daniels MJ, Garnett MJ, Venkitaraman AR. A mitotic function for the high-mobility group protein HMG20b regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor. Oncogene. 2011;30(30):3360–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang G, Mercado-Uribe I, Multani AS, Sen S, Shih IE, Wong KK, Liu J. Erratum: RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of aurora-A and BRCA2. Cancer. 2013;133(2):275–85.

    CAS  Google Scholar 

  27. Ryser S, Dizin E, Jefford CE, Delaval B, Gagos S, Christodoulidou A, Irminger-Finger I. Distinct roles of BARD1 isoforms in mitosis: full-length BARD1 mediates Aurora B degradation, cancer-associated BARD1β scaffolds Aurora B and BRCA2. Can Res. 2009;69(3):1125–34.

    Article  CAS  Google Scholar 

  28. Thorslund T, Esashi F, West SC. Interactions between human BRCA2 protein and the meiosis-specific recombinase DMC1. EMBO J. 2007;26(12):2915–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Park I, Lee HO, Choi E, Lee YK, Kwon MS, Min J, Lee H. Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation. J Cell Biol. 2013;202(2):295–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Welcsh PL, King MC. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet. 2001;10(7):705–13.

    Article  CAS  PubMed  Google Scholar 

  31. Johansson I, Killander F, Linderholm B, Hedenfalk I. Molecular profiling of male breast cancer–lost in translation? Int J Biochem Cell Biol. 2014;53:526–35.

    Article  CAS  PubMed  Google Scholar 

  32. Zahra AZ, Kadkhoda S, Behjati F, Moghaddam FA, Badiei A, Sirati F, Keyhani E. Mutation screening of BRCA genes in 10 Iranian males with breast cancer. Int J Mol Cell Med. 2016;5(2):114.

    Google Scholar 

  33. Ruddy KJ, Winer EP. Male breast cancer: risk factors, biology, diagnosis, treatment, and survivorship. Ann Oncol. 2013;24(6):1434–43.

    Article  CAS  PubMed  Google Scholar 

  34. Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004;22(4):735–42.

    Article  CAS  PubMed  Google Scholar 

  35. Hilton JL, Geisler JP, Rathe JA, Hattermann-Zogg MA, DeYoung B, Buller RE. Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst. 2002;94(18):1396–406.

    Article  CAS  PubMed  Google Scholar 

  36. Lancaster JM, Wooster R, Mangion J, Phelan CM, Cochran C, Gumbs C, Patel S. BRCA2 mutations in primary breast and ovarian cancers. Nat Genet. 1996;13(2):238–40.

    Article  CAS  PubMed  Google Scholar 

  37. Edwards SM, Kote-Jarai Z, Meitz J, Hamoudi R, Hope Q, Osin P, Dearnaley DP. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003;72(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  38. Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Kern SE. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Can Res. 1996;56(23):5360–4.

    CAS  Google Scholar 

  39. Karami F, Mehdipour PA. Comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. BioMed Res Int. 2013;201:1–21.

    Article  Google Scholar 

  40. Biswas K, Das R, Eggington JM, Qiao H, North SL, Stauffer S, Pruss D. Functional evaluation of BRCA2 variants mapping to the PALB2 binding and C-terminal DNA binding domains using a mouse ES cell-based assay. Hum Mol Genet. 2012;21:3993–4006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Antoniou A, Pharoah PDP, Narod S, Risch HA, Eyfjord JE, Hopper JL, Pasini B. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ferla R, Calo V, Cascio S, Rinaldi G, Badalamenti G, Carreca I, Russo A. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007;18(6):93–8.

    Google Scholar 

  43. Neuhausen SL, Godwin AK, Gershoni-Baruch R, Schubert E, Garber J, Stoppa-Lyonnet D, Osorio A. Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. Am J Hum Genet. 1998;62(6):1381–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tonin PN, Mes-Masson AM, Futreal PA, Morgan K, Mahon M, Foulkes WD, Narod SA. Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. Am J Hum Genet. 1998;63(5):1341–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Campos B, Diez O, Domenech M, Baena M, Pericay C, Balmana J, Baiget M. BRCA2 mutation analysis of 87 Spanish breast/ovarian cancer families. Ann Oncol. 2001;12(12):1699–703.

    Article  CAS  PubMed  Google Scholar 

  46. Liede A, Narod SA. Hereditary breast and ovarian cancer in Asia: genetic epidemiology of BRCA1 and BRCA2. Hum Mutat. 2002;20(6):413–24.

    Article  CAS  PubMed  Google Scholar 

  47. Ang P, Lim A, Lee TC, Luo JT, Ong DC, Tan PH, Lee AS. BRCA1 and BRCA2 mutations in an Asian clinic-based population detected using a comprehensive strategy. Cancer Epidemiol Prev Biomark. 2007;16(11):2276–84.

    Article  CAS  Google Scholar 

  48. Zhi X, Szabo C, Chopin S, Suter N, Wang QS, Ostrander EA, Shi YR. BRCA1 and BRCA2 sequence variants in Chinese breast cancer families. Hum Mutat. 2002;20(6):474.

    Article  PubMed  Google Scholar 

  49. Liede A, Malik IA, Aziz Z, De los Rios P, Kwan E, Narod SA. Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan. Am J Hum Genet. 2002;71(3):595–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Farooq A, Naveed AK, Azeem Z, Ahmad T. Breast and ovarian cancer risk due to prevalence of BRCA1 and BRCA2 variants in Pakistani population: a Pakistani database report. J Oncol. 2011; 2011:1–8.

    Article  Google Scholar 

  51. Seo JH, Cho DY, Ahn SH, Yoon KS, Kang CS, Cho HM, Shin SW. BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer. Hum Mutat. 2004;24(4):350.

    Article  PubMed  Google Scholar 

  52. Pietschmann A, Mehdipour P, Atri M, Hofmann W, Hosseini-Asl SS, Scherneck S, Peters H. Mutation analysis of BRCA1 and BRCA2 genes in Iranian high risk breast cancer families. J Cancer Res Clin Oncol. 2005;131(8):552–8.

    Article  CAS  PubMed  Google Scholar 

  53. Rytelewski M, Ferguson PJ, Vareki SM, Figueredo R, Vincent M, Koropatnick J. Inhibition of BRCA2 and thymidylate synthase creates multidrug sensitive tumor cells via the induction of combined “complementary lethality”. Mol Ther Nucleic Acids. 2013;2(3):e78.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Sessa C. Update on PARP1 inhibitors in ovarian cancer. Ann Oncol. 2011;22(8):viii72–6.

    PubMed  Google Scholar 

  55. Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10(4):293–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase. Nature. 2005;434(7035):913–7.

    Article  CAS  PubMed  Google Scholar 

  57. Venkitaraman AR. Targeting the molecular defect in BRCA-deficient tumors for cancer therapy. Cancer Cell. 2009;16(2):89–90.

    Article  CAS  PubMed  Google Scholar 

  58. Evers B, Drost R, Schut E, de Bruin M, van der Burg E, Derksen PW, Smith GC. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin Cancer Res. 2008;14(12):3916–25.

    Article  CAS  PubMed  Google Scholar 

  59. Zimmer J, Tacconi EM, Folio C, Badie S, Porru M, Klare K, Jackson SP. Targeting BRCA1 and BRCA2 deficiencies with G-quadruplex-interacting compounds. Mol Cell. 2016;61(3):449–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India

    Anjali Shailani, Raman Preet Kaur & Anjana Munshi

Authors
  1. Anjali Shailani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raman Preet Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anjana Munshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anjana Munshi.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shailani, A., Kaur, R.P. & Munshi, A. A comprehensive analysis of BRCA2 gene: focus on mechanistic aspects of its functions, spectrum of deleterious mutations, and therapeutic strategies targeting BRCA2-deficient tumors. Med Oncol 35, 18 (2018). https://doi.org/10.1007/s12032-018-1085-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-018-1085-8

Keywords

Search

Navigation