Skip to main content

Advertisement

SpringerLink
Log in

A polymorphism in the promoter region of Ku70/XRCC6, associated with breast cancer risk and oestrogen exposure

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Polymorphisms in double strand break repair genes could be involved in genetic breast cancer predisposition as enhanced chromosomal radiosensitivity is a hallmark for breast cancer. Previously, the c.-1310 C>G SNP, located in the Ku70 promoter, showed a significant odds ratio (OR) of 1.85 (P = 0.048) in sporadic, but not familial breast cancer patients, indicating that other factors besides genetic aptitude influence this association. As breast epithelium is exposed to endogenous oxidative stress through oestrogen exposure, the influence of hormone exposure was further examined.

Methods and results

A significant OR (1.69, P = 0.017) was found for an enlarged patient population through PCR-RFLP assays in a case–control study in a Belgian population. After dividing the patient population according to oestrogen exposure, high and significant ORs were seen for patients with a longer oestrogen exposure (late age at menopause: OR = 1.96, P = 0.029).

Conclusion

These results show that the variant allele of c.-1310 C>G, located in the Ku70 promoter, is a risk allele for breast cancer. Furthermore, the association of the c.-1310 C>G SNP with breast cancer risk was stronger in women with a long oestrogen exposure.

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
Fig. 4

Similar content being viewed by others

References

  • Baeyens A, Thierens H, Claes K, Poppe B, Messiaen L, De Ridder L, Vral A (2002) Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition. Br J Cancer 87:1379–1385. doi:10.1038/sj.bjc.6600628

    Article  PubMed  CAS  Google Scholar 

  • Baeyens A, Van Den Broecke R, Makar A, Thierens H, De Ridder L, Vral A (2005) Chromosomal radiosensitivity in breast cancer patients: influence of age of onset of the disease. Oncol Rep 13:347–353

    PubMed  Google Scholar 

  • Banerjee S, Smith S, Myung K (2006) Suppression of gross chromosomal rearrangements by yKu70-yKu80 heterodimer through DNA damage checkpoints. Proc Natl Acad Sci USA 103:1816–1821. doi:10.1073/pnas.0504063102

    Article  PubMed  CAS  Google Scholar 

  • Bau D, Fu Y, Chen S, Cheng T, Yu J, Wu P, Shen C (2004) Breast cancer risk and the DNA double-strand break end-joining capacity of nonhomologous end-joining gens are affected by BRCA1. Cancer Res 64:5013–5019. doi:10.1158/0008-5472.CAN-04-0403

    Article  PubMed  CAS  Google Scholar 

  • Bau D, Mau Y, Ding S, Wu P, Shen C (2007) DNA double-strand break repair capacity and risk of breast cancer. Carcinogenesis 28:1726–1730. doi:10.1093/carcin/bgm109

    Article  PubMed  CAS  Google Scholar 

  • Belzile J, Choudhury S, Cournoyer D, Chow T (2006) Targeting DNA repair proteins: a promising avenue for cancer gene therapy. Curr Gene Ther 6:111–123. doi:10.2174/156652306775515538

    Article  PubMed  CAS  Google Scholar 

  • Chen C, Bhalala H, Qiao H, Dong J (2002) Possible tumor suppressor role of the KLF5 transcription factor in human breast cancer. Oncogene 21:6567–6572. doi:10.1038/sj.onc.1205817

    Article  PubMed  CAS  Google Scholar 

  • Cheng T, Chen S, Huang C, Fu Y, Yu J, Cheng C, Wu P, Shen C (2005) Breast cancer risk associated with genotype polymorphism of the catechol estrogen-metabolizing genes: a multigenic study on cancer susceptibility. Int J Cancer 113:345–353. doi:10.1002/ijc.20630

    Article  PubMed  CAS  Google Scholar 

  • Clarke R, Anderson E, Howell A (2004) Steroid receptors in human breast cancer. Trends Endocrinol Metab 15:316–323. doi:10.1016/j.tem.2004.07.004

    Article  PubMed  CAS  Google Scholar 

  • Downs J, Jackson S (2004) A means to a DNA end: the many roles of Ku. Nat Rev Mol Cell Biol 5:367–378. doi:10.1038/nrm1367

    Article  PubMed  CAS  Google Scholar 

  • Dunning AM, Healey CS, Pharoah PD, Teare MD, Ponder BA, Easton DF (1999) A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8:843–854

    PubMed  CAS  Google Scholar 

  • Fu Y, Yu J, Cheng T, Lou M, Hsu G, Wu C, Chen S, Wu H, Wu P, Shen C (2003) Breast cancer risk associated with genotypic polymorphism of the nonhomologous end-joining genes: a multigenic study on cancer susceptibility. Cancer Res 63:2440–2446

    PubMed  CAS  Google Scholar 

  • Gullo C, Au M, Feng G, Teoh G (2006) The biology of Ku and its potential oncogenic role in cancer. Biochim Biophys Acta 1765:223–234

    PubMed  CAS  Google Scholar 

  • Hasan N, MacDonald M (2002) Sp/Krüppel-like transcription factors are essential for the expression of mitochondrial glycerol phosphate dehydrogenase promoter B. Gene 296:221–234. doi:10.1016/S0378-1119(02)00865-X

    Article  PubMed  CAS  Google Scholar 

  • Hosoi Y, Watanabe T, Nakagawa K, Matsumoto Y, Enomoto A, Morita A, Nagawa H, Suzuki N (2004) Up-regulation of DNA-dependent protein kinase activity and Sp1 in colorectal cancer. Int J Oncol 25:461–468

    PubMed  CAS  Google Scholar 

  • Iliakis G, Wang H, Perrault AR, Boecker W, Rosidi B, Windhofer F, Wu W, Guan J, Terdouzi G, Pantelias G (2004) Mechanisms of DNA double strand break repair and chromosome aberration formation. Cytogenet Genome Res 104:14–20. doi:10.1159/000077461

    Article  PubMed  CAS  Google Scholar 

  • Jones L, Scott D, Cowan R, Roberts S (1995) Abnormal radiosensitivity of lymphocytes from breast-cancer patients with excessive normal tissue-damage after radiotherapy—chromosome-aberrations after low dose-rate irradiation. Int J Radiat Biol 67:519–528. doi:10.1080/09553009514550631

    Article  PubMed  CAS  Google Scholar 

  • Karunagaran D, Rashmi R, Santhosh K (2005) Induction of apoptosis by Curcumen and its implications for cancer therapy. Curr Cancer Drug Targets 5:117–129. doi:10.2174/1568009053202081

    Article  PubMed  CAS  Google Scholar 

  • Kennedy R, Quinn J, Mullan P, Johnston P, Harkin D (2004) Role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst 96:1659–1668

    Article  PubMed  CAS  Google Scholar 

  • Khanna K, Jackson S (2001) DNA double-strand breaks: signalling, repair and the cancer connection. Nat Genet 27:247–254. doi:10.1038/85798

    Article  PubMed  CAS  Google Scholar 

  • Kuschel B, Auranen A, McBride S, Novik K, Antoniou A, Lipscombe J, Day N, Easton D, Ponder B, Pharoah P, Dunning A (2002) Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet 11:1399–1407. doi:10.1093/hmg/11.12.1399

    Article  PubMed  CAS  Google Scholar 

  • Lieber M, Ma Y, Pannicke U, Schwarz K (2003) Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol 4:712–720. doi:10.1038/nrm1202

    Article  PubMed  CAS  Google Scholar 

  • McPherson K, Steel C, Dixon J (2000) ABC of breast diseases. Breast cancer-epidemiology, risk factors, and genetics. BMJ 321:624–628. doi:10.1136/bmj.321.7261.624

    Article  PubMed  CAS  Google Scholar 

  • Muller C, Paupert J, Monferran S, Salles B (2005) The double life of the Ku protein: facing the DNA breaks and the extracellular environment. Cell Cycle 4:438–441

    PubMed  CAS  Google Scholar 

  • Nathanson KN, Wooster R, Weber BL (2001) Breast cancer genetics: what we know and what we need. Nat Med 7:552–556. doi:10.1038/87876

    Article  PubMed  CAS  Google Scholar 

  • NCBI. http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=2267437. Retrieved Nov 2008

  • Nowacka-Zawiszac M, Brys M, Romanowicz-Makowska H, Kulig A, Krajewska W (2008) Dinucleotide repeat polymorphisms of RAD51, BRCA1, BRCA2 gene regions in breast cancer. Pathol Int 58:275–281. doi:10.1111/j.1440-1827.2008.02223.x

    Article  CAS  Google Scholar 

  • Pearce S, Jordan V (2004) The biological role of estrogen receptors alpha and beta in cancer. Crit Rev Oncol Hematol 50:3–22. doi:10.1016/j.critrevonc.2003.09.003

    Article  PubMed  Google Scholar 

  • Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, Easton D, Evans C, Deacon J, Stratton M (1999) Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 91:943–949. doi:10.1093/jnci/91.11.943

    Article  PubMed  CAS  Google Scholar 

  • Pfeiffer P, Goedecke W, Kuhfittig-Kulle S, Obe G (2004) Pathways of DNA double-strand break repair and their impact on the prevention and formation of chromosomal aberrations. Cytogenet Genome Res 104:7–13. doi:10.1159/000077460

    Article  PubMed  CAS  Google Scholar 

  • Pucci S, Mazzarelli P, Rabitti C, Giai M, Gallucci M, Flammia G, Alcini A, Altomare V, Fazio V (2001) Tumor specific modulation of KU70/80 DNA binding activity in breast and bladder human tumor biopsies. Oncogene 20:739–747. doi:10.1038/sj.onc.1204148

    Article  PubMed  CAS  Google Scholar 

  • Ralhan R, Kaur J, Kreienberg R, Wiesmüller L (2007) Links between DNA double strand break repair and breast cancer: accumulating evidence from both familial and nonfamilial cases. Cancer Lett 248:1–17. doi:10.1016/j.canlet.2006.06.004

    Article  PubMed  CAS  Google Scholar 

  • Rebbeck T (1999) Inherited genetic predisposition in breast cancer—a population-based perspective. Cancer 86:2493–2501. doi:10.1002/(SICI)1097-0142(19991201)86:11+<2493::AID-CNCR6>3.0.CO;2-Z

    Article  PubMed  CAS  Google Scholar 

  • Reis-Filho J, Tutt A (2008) Triple negative tumours: a critical review. Histopathology 52:108–118. doi:10.1111/j.1365-2559.2008.03046.x

    Article  PubMed  CAS  Google Scholar 

  • Roy D, Cai Q, Felty Q, Narayan S (2007) Estrogen-induced generation of reactive oxygen and nitrogen species, gene damage, and estrogen-dependent cancers. J Toxicol Environ Health B Crit Rev 10:235–257. doi:10.1080/15287390600974924

    PubMed  CAS  Google Scholar 

  • Rozenblum E, Vahteristo P, Sandberg T, Bergthorsson J, Syrjakoski K, Weaver D, Haraldsson K, Johannsdottir H, Vehmanen P, Nigam S, Golberger N, Robbins C, Pak E, Dutra A, Gillander E, Stephan D, Bailey-Wilson J, Juo S, Kainu T, Arason A, Barkardottir R, Nevanlinna H, Borg A, Kallioniemi O (2002) A genomic map of a 6-Mb region at 13q21-q22 implicated in cancer development: identification and characterization of candidate genes. Hum Genet 110:111–121. doi:10.1007/s00439-001-0646-6

    Article  PubMed  CAS  Google Scholar 

  • Russo J, Hasan LM, Balogh G, Guo S, Russo I (2003) Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. J Steroid Biochem Mol Biol 87:1–25. doi:10.1016/S0960-0760(03)00390-X

    Article  PubMed  CAS  Google Scholar 

  • Salles B, Calsou P, Frit P, Muller C (2006) The DNA repair complex DNA-PK, a pharmacological target in cancer chemotherapy and radiotherapy. Pathol Biol 54:185–193. doi:10.1016/j.patbio.2006.01.012

    Article  PubMed  CAS  Google Scholar 

  • Sang-Wook L, Kyung-Ja C, Jin-Hong P, Sang Y, Soon Y, Bong-Jae L, Sing-Bae K, Seung-Ho C, Jong H, Seong S, Eun K, Eunsil Y (2005) Expressions of Ku70 and DNA-PKCS as prognostic indicators of local control of nasopharyngeal carcinoma. Int J Radiat Oncol 62:1451–1457. doi:10.1016/j.ijrobp.2004.12.049

    Article  CAS  Google Scholar 

  • Scott D, Barber J, Levine E, Burrill W, Roberts S (1998) Radiation-induced micronucleus induction in lymphocytes identifies a high frequency of radiosensitive cases among breast cancer patients: a test for predisposition? Br J Cancer 77:614–620

    PubMed  CAS  Google Scholar 

  • Scott D, Barber J, Spreadborough A, Burrill W, Roberts S (1999) Increased chromosomal radiosensitivity in breast cancer patients: a comparison of two assays. Int J Radiat Biol 75:1–10. doi:10.1080/095530099140744

    Article  PubMed  CAS  Google Scholar 

  • Someya M, Sakata K, Matsumot Y, Tauchi H, Narimatsu H, Hareyama M (2007) Association of DNA-PK activity and radiation-induced NBS1 foci formation in lymphocytes with clinicla malignancy in breast cancer patients. Oncol Rep 18:873–878

    PubMed  CAS  Google Scholar 

  • Teare M, Wallace S, Harris M, Howell A, Birch J (1994) Cancer experience in the relatives of an unselected series of breast-cancer patients. Br J Cancer 70:102–111

    PubMed  CAS  Google Scholar 

  • Tutt A, Ashworth A (2002) The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med 8:571–576. doi:10.1016/S1471-4914(02)02434-6

    Article  PubMed  CAS  Google Scholar 

  • Valerie K, Povirk L (2003) Regulation and mechanisms of mammalian double-strand break repair. Oncogene 22:5792–5812. doi:10.1038/sj.onc.1206679

    Article  PubMed  CAS  Google Scholar 

  • Willems P, Claes K, Baeyens A, Vandersickel V, Werbrouck J, De Ruyck K, Poppe B, Van den Broecke R, Makar A, Marras E, Perletti G, Thierens H, Vral A (2008) Polymorphisms in nonhomologous end-joining genes associated with breast cancer risk and chromosomal radiosensitivity. Genes Chromosom Cancer 47:137–148

    Article  PubMed  CAS  Google Scholar 

  • Wilson C, Davidson S, Margison G, Jackson S, Hendry J, West C (2000) Expression of Ku70 correlates with survival in carcinoma of the cervix. Br J Cancer 83:1702–1706. doi:10.1054/bjoc.2000.1510

    Article  PubMed  CAS  Google Scholar 

  • Yager J, Davidson N (2006) Mechanisms of disease: estrogen carcinogenesis in breast cancer. N Engl J Med 354:270–282. doi:10.1056/NEJMra050776

    Article  PubMed  CAS  Google Scholar 

  • Zhang C, Naftalis E, Euhus D (2006) Carcinogen-induced DNA double strand break repair in sporadic breast cancer. J Surg Res 135:120–128. doi:10.1016/j.jss.2006.02.057

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work was supported by a grant of the “Bijzonder Onderzoeksfonds” (Gent University, No B/05780/01). The authors declare that we have no conflict of interest. We wish to thank all the patients and volunteers who participated in this study.

Author information

Authors and Affiliations

  1. Department of Basic Medical Science, Ghent University, De Pintelaan 185 (6B3), 9000, Ghent, Belgium

    Petra Willems, Kim De Ruyck, Hubert Thierens & Anne Vral

  2. Department of Gynaecological Oncology, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium

    Rudy Van den Broecke & Amin Makar

  3. Department of Gynaecological Oncology, Middelheim Hospital, Lindendreef 1, 2020, Antwerp, Belgium

    Amin Makar

  4. Department of Structural and Functional Biology, University of Insubria, via A. da Giussano 12, 21052, Busto Arsizio, Italy

    Gianpaolo Perletti

Authors
  1. Petra Willems
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kim De Ruyck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rudy Van den Broecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amin Makar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gianpaolo Perletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hubert Thierens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anne Vral
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anne Vral.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Willems, P., De Ruyck, K., Van den Broecke, R. et al. A polymorphism in the promoter region of Ku70/XRCC6, associated with breast cancer risk and oestrogen exposure. J Cancer Res Clin Oncol 135, 1159–1168 (2009). https://doi.org/10.1007/s00432-009-0556-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-009-0556-x

Keywords

Search

Navigation