Skip to main content

Advertisement

SpringerLink
Log in

Quantitative analysis of mitochondrial DNA 4977-bp deletion in sporadic breast cancer and benign breast diseases

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The mitochondrial DNA (mtDNA) 4977-bp deletion (ΔmtDNA4977 mutation) is one of the most frequently observed mtDNA mutations in human tissues and may play a role in carcinogenesis. Only a few studies have evaluated ΔmtDNA4977 mutation in breast cancer tissue, and the findings have been inconsistent, which may be due to methodological differences. In this study, we developed a quantitative real-time PCR assay to assess the level of the ΔmtDNA4977 mutation in tumor tissue samples from 55 primary breast cancer patients and 21 patients with benign breast disease (BBD). The ΔmtDNA4977 mutation was detected in all of the samples with levels varying from 0.000149% to 7.0%. The ΔmtDNA4977 mutation levels were lower in tumor tissues than in adjacent normal tissues in both breast cancer and BBD subjects. The differences, however, were not statistically significant. No significant difference between breast cancer and BBD patients was found in the ΔmtDNA4977 mutation levels of tumor tissues and adjacent normal tissues. The ΔmtDNA4977 mutation levels were not significantly associated with clinicopathological characteristics (age, histology, tumor stage, and ER/PR status) in breast cancer or BBD patients. These results do not support the notion that the mitochondrial DNA 4977-bp deletion plays a major role in breast carcinogenesis.

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

Similar content being viewed by others

References

  1. Zhu W, Qin W, Bradley P, Wessel A, Puckett CL, Sauter ER (2005) Mitochondrial DNA mutations in breast cancer tissue and in matched nipple aspirate fluid. Carcinogenesis 26:145–152

    Article  PubMed  CAS  Google Scholar 

  2. Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N (1999) Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 23:147

    Article  PubMed  CAS  Google Scholar 

  3. Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465

    Article  PubMed  CAS  Google Scholar 

  4. Dani MA, Dani SU, Lima SP, Martinez A, Rossi BM, Soares F, Zago MA, Simpson AJ (2004) Less Deltamt DNA4977 than normal in various types of tumors suggests that cancer cells are essentially free of this mutation. Genet Mol Res 3:395–409

    PubMed  CAS  Google Scholar 

  5. Tan DJ, Chang J, Liu LL, Bai RK, Wang YF, Yeh KT, Wong LJ (2006) Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer. BMC Cancer 6:93

    Article  PubMed  CAS  Google Scholar 

  6. Roy D, Liehr JG (1999) Estrogen, DNA damage and mutations. Mutat Res 424:107–115

    PubMed  CAS  Google Scholar 

  7. Bianchi MS, Bianchi NO, Bailliet G (1995) Mitochondrial DNA mutations in normal and tumor tissues from breast cancer patients. Cytogenet Cell Genet 71:99–103

    PubMed  CAS  Google Scholar 

  8. Tseng LM, Yin PH, Chi CW, Hsu CY, Wu CW, Lee LM, Wei YH, Lee HC (2006) Mitochondrial DNA mutations and mitochondrial DNA depletion in breast cancer. Genes Chromosomes Cancer 45:629–638

    Article  PubMed  CAS  Google Scholar 

  9. Zhu W, Qin W, Sauter ER (2004) Large-scale mitochondrial DNA deletion mutations and nuclear genome instability in human breast cancer. Cancer Detect Prev 28:119–126

    Article  PubMed  CAS  Google Scholar 

  10. Gao YT, Shu XO, Dai Q, Potter JD, Brinton LA, Wen W, Sellers TA, Kushi LH, Ruan Z, Bostick RM, Jin F, Zheng W (2000) Association of menstrual and reproductive factors with breast cancer risk: results from the Shanghai Breast Cancer Study. Int J Cancer 87:295–300

    Article  PubMed  CAS  Google Scholar 

  11. Schnitt S, Connolly J (1999) Pathology of benign breast disorders In: Harris JR, Lippman ME, Morrow M, Osborne CK (eds) Diseases of the breast. Lippincott Williams & Wilkins, Philadelphia, pp 75–93

    Google Scholar 

  12. Levin BC, Holland KA, Hancock DK, Coble M, Parsons TJ, Kienker LJ, Williams DW, Jones M, Richie KL (2003) Comparison of the complete mtDNA genome sequences of human cell lines—HL-60 and GM10742A—from individuals with pro-myelocytic leukemia and leber hereditary optic neuropathy, respectively, and the inclusion of HL-60 in the NIST human mitochondrial DNA standard reference material—SRM 2392-I. Mitochondrion 2:387–400

    Article  PubMed  CAS  Google Scholar 

  13. Hirakawa M, Tanaka T, Hashimoto Y, Kuroda M, Takagi T, Nakamura Y (2002) JSNP: a database of common gene variations in the Japanese population. Nucleic Acids Res 30:158–162

    Article  PubMed  CAS  Google Scholar 

  14. Smigielski EM, Sirotkin K, Ward M, Sherry ST (2000) dbSNP: a database of single nucleotide polymorphisms. Nucleic Acids Res 28:352–355

    Article  PubMed  CAS  Google Scholar 

  15. Pushnova EA, Geier M, Zhu YS (2000) An easy and accurate agarose gel assay for quantitation of bacterial plasmid copy numbers. Anal Biochem 284:70–76

    Article  PubMed  CAS  Google Scholar 

  16. Chuanzhong Y, Ming G, Fanglin Z, Haijiao C, Zhen L, Shiping C, Yong Kang Z (2002) Real-time quantitative reverse transcription-PCR assay for renal cell carcinoma-associated antigen G250. Clin Chim Acta 318:33–40

    Article  PubMed  Google Scholar 

  17. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  18. Shieh DB, Chou WP, Wei YH, Wong TY, Jin YT (2004) Mitochondrial DNA 4,977-bp deletion in paired oral cancer and precancerous lesions revealed by laser microdissection and real-time quantitative PCR. Ann NY Acad Sci 1011:154–167

    Article  PubMed  CAS  Google Scholar 

  19. Pogozelski WK, Hamel CJ, Woeller CF, Jackson WE, Zullo SJ, Fischel-Ghodsian N, Blakely WF (2003) Quantification of total mitochondrial DNA and the 4977-bp common deletion in Pearson’s syndrome lymphoblasts using a fluorogenic 5′-nuclease (TaqMan) real-time polymerase chain reaction assay and plasmid external calibration standards. Mitochondrion 2:415–427

    Article  PubMed  CAS  Google Scholar 

  20. He L, Chinnery PF, Durham SE, Blakely EL, Wardell TM, Borthwick GM, Taylor RW, Turnbull DM (2002) Detection and quantification of mitochondrial DNA deletions in individual cells by real-time PCR. Nucleic Acids Res 30:e68

    Article  PubMed  Google Scholar 

  21. Nicklas JA, Brooks EM, Hunter TC, Single R, Branda RF (2004) Development of a quantitative PCR (TaqMan) assay for relative mitochondrial DNA copy number and the common mitochondrial DNA deletion in the rat. Environ Mol Mutagen 44:313–320

    Article  PubMed  CAS  Google Scholar 

  22. Kakiuchi C, Ishiwata M, Kametani M, Nelson C, Iwamoto K, Kato T (2005) Quantitative analysis of mitochondrial DNA deletions in the brains of patients with bipolar disorder and schizophrenia. Int J Neuropsychopharmacol 8:515–522

    Article  PubMed  CAS  Google Scholar 

  23. Porteous WK, James AM, Sheard PW, Porteous CM, Packer MA, Hyslop SJ, Melton JV, Pang CY, Wei YH, Murphy MP (1998) Bioenergetic consequences of accumulating the common 4977-bp mitochondrial DNA deletion. Eur J Biochem 257:192–201

    Article  PubMed  CAS  Google Scholar 

  24. Schoeler S, Szibor R, Gellerich FN, Wartmann T, Mawrin C, Dietzmann K, Kirches E (2005) Mitochondrial DNA deletions sensitize cells to apoptosis at low heteroplasmy levels. Biochem Biophys Res Commun 332:43–49

    Article  PubMed  CAS  Google Scholar 

  25. Shao JY, Gao HY, Li YH, Zhang Y, Lu YY, Zeng YX (2004) Quantitative detection of common deletion of mitochondrial DNA in hepatocellular carcinoma and hepatocellular nodular hyperplasia. World J Gastroenterol 10:1560–1564

    PubMed  CAS  Google Scholar 

  26. Shao JY, Li YH, Gao HY, Mai HQ, Zhang Y, Guo X, Zeng YX (2004) High frequency of common deletion (4981 bp) in mitochondrial DNA in nasopharyngeal carcinoma and its correlation with patient age and clinical stages. Cancer Biol Ther 3:1270–1274

    Article  PubMed  CAS  Google Scholar 

  27. Rogounovitch TI, Saenko VA, Shimizu-Yoshida Y, Abrosimov AY, Lushnikov EF, Roumiantsev PO, Ohtsuru A, Namba H, Tsyb AF, Yamashita S (2002) Large deletions in mitochondrial DNA in radiation-associated human thyroid tumors. Cancer Res 62:7031–7041

    PubMed  CAS  Google Scholar 

  28. Lewis PD, Baxter P, Paul GA, Parry JM, Skibinski DO (2000) Detection of damage to the mitochondrial genome in the oncocytic cells of Warthin’s tumour. J Pathol 191:274–281

    Article  PubMed  CAS  Google Scholar 

  29. Yin PH, Lee HC, Chau GY, Wu YT, Li SH, Lui WY, Wei YH, Liu TY, Chi CW (2004) Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma. Br J Cancer 90:2390–2396

    PubMed  CAS  Google Scholar 

  30. Wu CW, Yin PH, Hung WY, Li AF, Li SH, Chi CW, Wei YH, Lee HC (2005) Mitochondrial DNA mutations and mitochondrial DNA depletion in gastric cancer. Genes Chromosomes Cancer 44:19–28

    Article  PubMed  CAS  Google Scholar 

  31. Lee HC, Yin PH, Yu TN, Chang YD, Hsu WC, Kao SY, Chi CW, Liu TY, Wei YH (2001) Accumulation of mitochondrial DNA deletions in human oral tissues—effects of betel quid chewing and oral cancer. Mutat Res 493:67–74

    PubMed  CAS  Google Scholar 

  32. Yang JH, Lee HC, Chung JG, Wei YH (2004) Mitochondrial DNA mutations in light-associated skin tumors. Anticancer Res 24:1753–1758

    PubMed  CAS  Google Scholar 

  33. Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA (2004) Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res 64:985–993

    Article  PubMed  CAS  Google Scholar 

  34. Jia L, Liu KZ, Newland AC, Mantsch HH, Kelsey SM (1999) Pgp-positive leukaemic cells have increased mtDNA but no increased rate of proliferation. Br J Haematol 107:861–869

    Article  PubMed  CAS  Google Scholar 

  35. Han YC, Kong WJ, Zhang S, Wang YJ, Wang Y, Chen X (2004) Mutation of mitochondrial DNA 4977 bp deletion in laryngeal squamous cell cancer. Ai Zheng 23:1297–1301

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Konrad Huppi (Cancer Prevention Studies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD) for kindly providing mitochondrial DNA samples, Bethanie Hull and Brandy Venuti for technical assistance in the preparation of this article, and all of the study participants and research staff of the Shanghai Breast Cancer Study for their support. This research was supported by U.S. Department of Defense grant DAMD17-02-1-0603 and National Cancer Institute grant R01 CA064277.

Author information

Authors and Affiliations

  1. Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine and Vanderbilt Ingram-Cancer Center, Nashville, TN, 37232, USA

    Chuanzhong Ye, Xiao-Ou Shu, Wanqing Wen, Larry Pierce, Regina Courtney, Wei Zheng & Qiuyin Cai

  2. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, P.R. China

    Yu-Tang Gao

Authors
  1. Chuanzhong Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Ou Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wanqing Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Larry Pierce
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Regina Courtney
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu-Tang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qiuyin Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qiuyin Cai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ye, C., Shu, XO., Wen, W. et al. Quantitative analysis of mitochondrial DNA 4977-bp deletion in sporadic breast cancer and benign breast diseases. Breast Cancer Res Treat 108, 427–434 (2008). https://doi.org/10.1007/s10549-007-9613-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-007-9613-9

Keywords

Search

Navigation