Abstract
Mitochondrial DNA (mtDNA) mutations are frequent in breast tumors, but the etiology of these mutations is unknown. We hypothesized that these mutations are associated with exposures that affect oxidative stress such as alcohol metabolism. Using archived tumor blocks from incident breast cancer cases in a case control study, the Western New York Exposures and Breast Cancer (WEB) study, analysis of mtDNA mutations was conducted on 128 breast cancer cases selected based on extremes of alcohol intake. Temporal temperature gradient gel electrophoresis (TTGE) was used to screen the entire mtDNA genome and sequencing was completed for all TTGE positive samples. Case–case comparisons were completed using unconditional logistic regression to determine the relative prevalence of the mutations by exposures including alcohol consumption, manganese superoxide dismutase (MnSOD) genotype, nutrient intake related to oxidative stress and established breast cancer risk factors. Somatic mtDNA mutations were found in 60 of the 128 tumors examined. There were no differences in the prevalence of mtDNA mutations by alcohol consumption, MnSOD genotype or dietary intake. The likelihood of mtDNA mutations was reduced among those with a positive family history for breast cancer (OR = 0.33, CI = 0.12–0.92), among postmenopausal women who used hormone replacement therapy (OR = 0.46, CI = 0.19–1.08, P = 0.08) and was increased for ER negative tumors (OR = 2.05, CI = 0.95–4.43, P = 0.07). Consistent with previous studies, we found that mtDNA mutations are a frequent occurrence in breast tumors. An understanding of the etiology of mtDNA mutations may provide insight into breast carcinogenesis.
Similar content being viewed by others
References
Carew JS, Huang P (2002) Mitochondrial defects in cancer. Mol Cancer 1:1476–1488
Tan DJ, Bai RK, Wong LJ (2002) Comprehensive scanning of somatic mitochondrial DNA mutations in breast cancer. Cancer Res 62:972–976
Parrella P, Xiao Y, Fliss M et al (2001) Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates. Cancer Res 61:7623–7626
Zhu W, Qin W, Bradley P et al (2005) Mitochondrial DNA mutations in breast cancer tissue and in matched nipple aspirate fluid. Carcinogenesis 26:145–152
Ishii H, Kurose I, Kato S (1997) Pathogenesis of alcoholic liver disease with particular emphasis on oxidative stress. J Gastroenterol Hepatol 12:S272–S282
Lubec G (1996) The hydroxyl radical: from chemistry to human disease. J Investig Med 44:324–346
Kumaraguruparan R, Kabalimoorthy J, Nagini S (2005) Correlation of tissue lipid peroxidation and antioxidants with clinical stage and menopausal status in patients with adenocarcinoma of the breast. Clin Biochem 38:154–158
Soliman AS, Vulimiri SV, Kleiner HE et al (2004) High levels of oxidative DNA damage in lymphocyte DNA of premenopausal breast cancer patients from Egypt. Int J Environ Health Res 14:121–134
Tas F, Hansel H, Belce A et al (2005) Oxidative stress in breast cancer. Med Oncol 22:11–15
Yeh CC, Hou MF, Tsai SM et al (2005) Superoxide anion radical, lipid peroxides and antioxidant status in the blood of patients with breast cancer. Clin Chim Acta 361:104–111
Lieber CS (1997) Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases. Adv Pharmacol 38:601–628
Rosenblum JS, Gilula NB, Lerner RA (1996) On signal sequence polymorphisms and diseases of distribution. Proc Natl Acad Sci USA 93:4471–4473
Bag A, Bag N (2008) Target sequence polymorphism of human manganese superoxide dismutase gene and its association with cancer risk: a review. Cancer Epidemiol Biomarkers Prev 17:3298–3305
Tseng LM, Yin PH, Chi CW et al (2006) Mitochondrial DNA mutations and mitochondrial DNA depletion in breast cancer. Genes Chromosomes Cancer 45:629–638
Bonner MR, Han D, Nie J et al (2005) Breast cancer risk and exposure in early life to polycyclic aromatic hydrocarbons using total suspended particulates as a proxy measure. Cancer Epidemiol Biomarkers Prev 14:53–60
Block G, Hartman AM, Dresser CM et al (1986) A data-based approach to diet questionnaire design and testing. Am J Epidemiol 124:453–469
Willett WC, Howe GR, Kushi LH (1997) Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr 65:1220S–1228S discussion 1229S–1231S
Allred DC, Harvey JM, Berardo M et al (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168
Lum A, Le Marchand L (1998) A simple mouthwash method for obtaining genomic DNA in molecular epidemiological studies. Cancer Epidemiol Biomarkers Prev 7:719–724
Wang X, Myers A, Saiki RK et al (2002) Development and evaluation of a PCR-based, line probe assay for the detection of 58 alleles in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Clin Chem 48:1121–1123
Anderson S, Bankier AT, Barrell BG et al (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465
Xu J, Turner A, Little J et al (2002) Positive results in association studies are associated with departure from Hardy-Weinberg equilibrium: hint for genotyping error? Hum Genet 111:573–574
Hoek JB, Cahill A, Pastorino JG (2002) Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology 122:2049–2063
Sugano T, Handler JA, Yoshihara H et al (1990) Acute and chronic ethanol treatment in vivo increases malate-aspartate shuttle capacity in perfused rat liver. J Biol Chem 265:21549–21553
Cunningham CC, Coleman WB, Spach PI (1990) The effects of chronic ethanol consumption on hepatic mitochondrial energy metabolism. Alcohol Alcohol 25:127–136
Suzuki M, Toyooka S, Miyajima K et al (2003) Alterations in the mitochondrial displacement loop in lung cancers. Clin Cancer Res 9:5636–5641
Ambrosone CB, Freudenheim JL, Thompson PA et al (1999) Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer. Cancer Res 59:602–606
Bergman M, Ahnstrom M, Palmeback Wegman P et al (2005) Polymorphism in the manganese superoxide dismutase (MnSOD) gene and risk of breast cancer in young women. J Cancer Res Clin Oncol 131:439–444
Egan KM, Thompson PA, Titus-Ernstoff L et al (2003) MnSOD polymorphism and breast cancer in a population-based case-control study. Cancer Lett 199:27–33
Mitrunen K, Sillanpaa P, Kataja V et al (2001) Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk. Carcinogenesis 22:827–829
Slanger TE, Chang-Claude J, Wang-Gohrke S (2006) Manganese superoxide dismutase Ala-9Val polymorphism, environmental modifiers, and risk of breast cancer in a German population. Cancer Causes Control 17:1025–1031
Russell M, Marshall JR, Trevisan M et al (1997) Test-retest reliability of the cognitive lifetime drinking history. Am J Epidemiol 146:975–981
Acknowledgments
This work was funded in part by the Department of Defense grants number DAMD 170310446 and 170010417 and the National Institutes of Health grants number RO1CA092040, P50AA09802 and R25CA114101.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Platek, M.E., Shields, P.G., Tan, D. et al. Alcohol consumption and breast tumor mitochondrial DNA mutations. Breast Cancer Res Treat 121, 453–460 (2010). https://doi.org/10.1007/s10549-009-0587-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-009-0587-7