Novel mitochondrial mutations in the ATP6 and ATP8 genes in patients with breast cancer

Grzybowska-Szatkowska,Ludmiła; Ślaska,Brygida; Rzymowska,Jolanta; Brzozowska,Anna; Floriańczyk,Bolesław

doi:10.3892/mmr.2014.2471

Novel mitochondrial mutations in the ATP6 and ATP8 genes in patients with breast cancer

Authors:
- Ludmiła Grzybowska-Szatkowska
- Brygida Ślaska
- Jolanta Rzymowska
- Anna Brzozowska
- Bolesław Floriańczyk
View Affiliations

Affiliations: Department of Oncology, Medical University of Lublin, 20-090 Lublin, Poland, Department of Biological Bases of Animal Production, University of Life Sciences in Lublin, 20-950 Lublin, Poland , Department of Biology and Genetics, Medical University of Lublin, 20-093 Lublin, Poland, Department of Clinical Dietetics, Medical University of Lublin, 20-093 Lublin, Poland
Published online on: August 8, 2014 https://doi.org/10.3892/mmr.2014.2471
Pages: 1772-1778
Copyright: © Grzybowska-Szatkowska et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The role of the mitochondria in the process of carcinogenesis, mainly oxidative phosphorylation, mostly concerns their participation in the production of free radicals and ATP and in the process of apoptosis. The purpose of this study was to detect potential changes in the genes encoding the subunits 6 and 8 of the ATP synthase and their impact on the enzyme's biochemical properties, structure and function in patients with breast tumors. The tested material was mitochondrial DNA (mtDNA) isolated from specimens of ductal carcinoma (carcinoma ductale) Tp1-2Np0-1Mp0, blood and non-cancerous tissue of mammary gland (control), sampled from 50 patients who had been operated for breast cancer. In the case of missense-type changes in the mtDNA, protein prediction software was used to assess their effect on the biochemical properties of the protein, its structure and function. We identified 8 changes in the ATP6 gene in 36/50 examined breast cancer cell samples and 5 changes in the ATP8 gene (10/50). Most of them were homoplasmic changes of missense type. Four of the changes (A8439C, G8858C, C9130G and T9119G) had not been described in the literature before. The identified mutations and polymorphisms, especially those of missense type, can affect mitochondrial functions, especially if the conservative domain of the protein is concerned. Replacement of ‘wild-type’ mtDNA by mutated mtDNA can be an important event in carcinogenesis.

View Figures

View References

1	Wallace DC: Bioenergetics in human evolution and disease: implications for the origins of biological complexity and the missing genetic variation of common diseases. Philos Trans R Soc Lond B Biol Sci. 368:2012.02672013.
2	Féthière J, Venzke D, Diepholz M, et al: Building the stator of the yeast vacuolar-ATPase: specific interaction between subunits E and G. J Biol Chem. 279:40670–40676. 2004.PubMed/NCBI
3	Czarnecka A and Bartnik E: The role of the mitochondrial genome in ageing and carcinogenesis. J Aging Res. 2011:1364352011. View Article : Google Scholar : PubMed/NCBI
4	Grzybowska-Szatkowska L and Slaska B: Mitochondrial DNA and carcinogenesis (review). Mol Med Rep. 6:923–930. 2012.
5	Zhu W, Qin W, Bradley P, Wessel A, Puckett CL and Sauter ER: Mitochondrial DNA mutations in breast cancer tissue and in matched nipple aspirate fluid. Carcinogenesis. 26:145–152. 2005. View Article : Google Scholar : PubMed/NCBI
6	Thomas PD, Campbell MJ, Kejariwal A, Mi H, et al: PANTHER: A library of protein families and subfamilies indexed by function. Genome Res. 13:2129–2141. 2003. View Article : Google Scholar : PubMed/NCBI
7	Sonnhammer ELL, von Heijne G and Krogh A: A hidden Markov model for predicting transmembrane helices in protein sequences. Proc Int Conf Intell Syst Mol Biol; 6:175–182. 1998.
8	Finn RD, Mistry J, Tate J, Coggill P, et al: The Pfam protein families database. Nucleic Acids Res. 38:D211–D222. 2010. View Article : Google Scholar : PubMed/NCBI
9	Muñoz V and Serrano L: Elucidating the folding problem of helical peptides using empirical parameters. Nat Struct Mol Biol. 1:399–409. 1994.
10	Kyte J and Doolittle RF: A simple method for displaying the hydropathic character of a protein. J Mol Biol. 157:105–132. 1982. View Article : Google Scholar : PubMed/NCBI
11	Gasteiger E, Hoogland C, Gattiker A, Duvaud S, Wilkins MR, Appel RD and Bairoch A: Protein identification and analysis tools on the ExPASy server. The Proteomics Protocols Handbook. Walker JM: Humana Press; New York, NY: pp. 571–607. 2005, View Article : Google Scholar
12	Goldenberg O, Erez E, Nimrod G and Ben-Tal N: The ConSurf-DB: pre-calculated evolutionary conservation profiles of protein structures. Nucleic Acids Res. 37:D323–D327. 2009. View Article : Google Scholar : PubMed/NCBI
13	Glaser F, Pupko T, Paz I, Bell RE, Bechor-Shental D, Martz E and Ben-Tal N: ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information. Bioinformatics. 19:163–164. 2003. View Article : Google Scholar : PubMed/NCBI
14	Canter JA, Kallianpur AR, Parl FF and Millikan RC: Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res. 65:8028–8033. 2005.
15	Grzybowska-Szatkowska L and Slaska B: Polymorphisms in genes encoding mt-tRNA in female breast cancer in Poland. Mitochondrial DNA. 23:106–111. 2012. View Article : Google Scholar : PubMed/NCBI
16	Petros JA, Baumann AK, Ruiz-Pesini E, et al: MtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA. 102:719–724. 2005. View Article : Google Scholar : PubMed/NCBI
17	Brandon M, Baldi P and Wallace DC: Mitochondrial mutations in cancer. Oncogene. 25:4647–4662. 2006. View Article : Google Scholar
18	Jones JB, Song JJ, Hempen PM, Parmigiani G, Hruban RH and Kern SE: Detection of mitochondrial DNA mutations in pancreatic cancer offers a ‘mass’-ive advantage over detection of nuclear DNA mutations. Cancer Res. 61:1299–1304. 2001.PubMed/NCBI
19	Guo XG, Liu CT, Dai H and Guo QN: Mutations in the mitochondrial ATPase6 gene are frequent in human osteosarcoma. Exp Mol Pathol. 94:285–288. 2013. View Article : Google Scholar : PubMed/NCBI
20	Dasgupta S, Shao CB, Keane TE, et al: Detection of mitochondrial deoxyribonucleic acid alterations in urine from urothelial cells carcinoma patients. Int J Cancer. 131:158–164. 2012. View Article : Google Scholar
21	Habano W, Nakamura S and Sugai T: Microsatellite instability in the mitochondrial DNA of colorectal carcinomas: evidence for mismatch repair systems in mitochondrial genome. Oncogene. 17:1931–1937. 1998. View Article : Google Scholar : PubMed/NCBI
22	Liu VW, Shi HH, Cheung AN, et al: High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas. Cancer Res. 61:5998–6001. 2001.PubMed/NCBI
23	Slaska B, Grzybowska-Szatkowska L, Surdyka M, Nisztuk S, Rozanska D, Rozanski P, Smiech A and Orzelski M: Mitochondrial D-loop mutations and polymorphisms are connected with canine malignant cancers. Mitochondrial DNA. 25:238–243. 2014. View Article : Google Scholar : PubMed/NCBI
24	Slaska B, Grzybowska-Szatkowska L, Nisztuk S, Surdyka M and Rozanska D: Mitochondrial DNA polymorphism in genes encoding ND1, COI and CYTB in canine malignant cancers. Mitochondrial DNA. Oct 9–2013. View Article : Google Scholar
25	Hofhaus G and Gattermann N: Mitochondria harbouring mutant mtDNA - a cuckoo in the nest? Biol Chem. 380:871–877. 1999. View Article : Google Scholar : PubMed/NCBI
26	Aikhionbare FO, Mehrabi S, Kumaresan K, Zavareh M, Olatinwo M, Odunsi K and Partridge E: Mitochondrial DNA sequence variants in epithelial ovarian tumor subtypes and stages. J Carcinog. 6:12007. View Article : Google Scholar : PubMed/NCBI
27	Czarnecka AM, Krawczyk T, Zdrozny M, et al: Mitochondrial NADH-dehydrogenase subunit 3 (ND3) polymorphism (A10398G) and sporadic breast cancer in Poland. Breast Cancer Res Treat. 121:511–518. 2010. View Article : Google Scholar : PubMed/NCBI
28	Setiawan VW, Chu LH, John EM, et al: Mitochondrial DNA G10398A variant is not associated with breast cancer in African-American women. Cancer Genet Cytogenet. 181:16–19. 2008. View Article : Google Scholar : PubMed/NCBI
29	Liu VW, Wang Y, Yang HJ, et al: Mitochondrial DNA variant 16189T>C is associated with susceptibility to endometrial cancer. Hum Mutat. 22:173–174. 2003.