The role of mitochondria in the development of breast cancer

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

There is a hypothesis that mitochondrial dysfunction and mutations in the mitochondrial genome may play an important role in the carcinogenesis; however, despite many years of research, this issue is still the subject of scientific discussion. The review reflects modern views on the role of mitochondria and the mitochondrial genome in the development of breast cancer. Sources were searched in Pubmed and eLIBRARY.RU databases for the past 10 years and in article references. Articles were selected that contained data from case-control studies of breast cancer and studies of cybrid cells.

The survey of experimental and association studies has shown that the mitochondrial genome determines the characteristics of cellular metabolism in human populations at the global (by macrohaplogroups L, M, N), landscape (by haplogroups), population (by subhaplogroups), and individual levels (by SNPs, insertions, deletions) and can determine predisposition to cancer. Single nucleotide substitutions, deletions, and mitochondrial DNA copy number decline are not specific for breast cancer. Nevertheless, mitochondria have been experimentally shown to be directly involved in the development of malignant neoplasms in experimental animals. It is likely that mitochondrial involvement in carcinogenesis is associated with mitochondrial dysfunction, in which nuclear-mitochondrial relationships are disrupted. On the other hand, mutations with too strong effect, i.e., completely disrupting mitochondrial function, lose their tumorigenic potential. Mutations, deletions and changes in mitochondrial DNA copy number are undoubtedly associated with the development of breast cancer, being one of the most important elements of a complex web of numerous interactions.

About the authors

Dmitrii G. Tikhonov

M. K. Ammosov North-Eastern Federal University

Author for correspondence.
Email: tikhonov.dmitri@yandex.ru
ORCID iD: 0000-0003-3385-9471
SPIN-code: 5271-4123

Dr. Sci. (Med.), Professor

Russian Federation, 58 Belinskogo street, 677000 Yakutsk

Mikael M. Vinokurov

M. K. Ammosov North-Eastern Federal University

Email: mm.vinokurov@s-vfu.ru
ORCID iD: 0000-0002-1235-6560
SPIN-code: 8895-6455

Dr. Sci. (Med.), Professor

Russian Federation, 58 Belinskogo street, 677000 Yakutsk

Nadezhda S. Kipriyanova

M. K. Ammosov North-Eastern Federal University

Email: kiprinad2@mail.ru

Dr. Sci. (Med.)

Russian Federation, 58 Belinskogo street, 677000 Yakutsk

Maria V. Golubenko

Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences

Email: maria-golubenko@medgenetics.ru
ORCID iD: 0000-0002-7692-9954
SPIN-code: 5117-3684

Cand. Sci. (Biol.)

Russian Federation, Tomsk

References

  1. Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–314. doi: 10.1126/science.123.3191.309
  2. Panov AV, Golubenko MV, Darenskaya MA, Kolesnikov SI. The origin of mitochondria and their role in the evolution of life and human health. Acta Biomedica Scientifica. 2020;5(5):12–25. (In Russ). doi: 10.29413/ABS.2020-5.5.2
  3. Osellame LD, Blacker TS, Duchen MR. Cellular and molecular mechanisms of mitochondrial function. Best Pract Res Clin Endocrinol Metab. 2012;26(6):711–723. doi: 10.1016/j.beem.2012.05.003
  4. Miller FJ, Rosenfeldt FL, Zhang C, et al. Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: lack of change of copy number with age. Nucleic Acids Res. 2003;31(11):e61. doi: 10.1093/nar/gng060
  5. Rath S, Sharma R, Gupta R, et al. MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations. Nucleic Acids Res. 2021;49(D1):D1541–D1547. doi: 10.1093/nar/gkaa1011
  6. Andrews RM, Kubacka I, Chinnery PF, et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet. 1999;23(2):147. doi: 10.1038/13779
  7. Nicholls TJ, Minczuk M. In D-loop: 40 years of mitochondrial 7S DNA. Exp Gerontol. 2014;56:175–181. doi: 10.1016/j.exger.2014.03.027
  8. Anderson S, Bankier AT, Barrell BG, et al. Sequence and organization of the human mitochondrial genome. Nature. 1981;290(5806):457–465. doi: 10.1038/290457a0
  9. Jones DP, Lash LH. Introduction: criteria for assessing normal and abnormal mitochondrial function. Mitochondrial Dysfunction. 1993. P. 1–7.
  10. Senyilmaz D, Teleman AA. Chicken or the egg: Warburg effect and mitochondrial dysfunction. F1000Prime Rep. 2015;7:41. doi: 10.12703/P7-41
  11. Blohin NN, Peterson BE. Klinicheskaja onkologija. T. 1. Moscow; 1979. 696 p. (In Russ).
  12. Burck KB, Liu ET, Larrick JW. Oncogenes. London, Paris, Tokyo: Springer-Verlag; 1988. 311 p.
  13. Fujimura JH. The molecular biological bandwagon in cancer research: where social worlds meet. Social Problems. 1988;35(3):261–283. doi: 10.2307/800622
  14. Bret S. Fighting cancer by putting tumor cells on a diet [Internet]. NPR, 2016. [cited 2022 Jun 29]. Available from: https://www.iowapublicradio.org/2016-03-05/fighting-cancer-by-putting-tumor-cells-on-a-diet
  15. Seyfried T. Cancer as a metabolic disease : on the origin, management, and prevention of cancer. John Wiley & Sons; 2012. 448 p.
  16. Gyamfi J, Kim J, Choi J. Cancer as a metabolic disorder. Int J Mol Sci. 2022;23(3):1155. doi: 10.3390/ijms23031155
  17. Majérus M-A. The cause of cancer: the unifying theory. Advances in Cancer Biology — Metastasis. 2022;4:100034. doi: 10.1016/j.adcanc.2022.100034
  18. Majerus MA. The relationship between the cancer cell and the oocyte. Med Hypotheses. 2002;58(6):544–551. doi: 10.1054/mehy.2001.1532
  19. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363–2376. doi: 10.1056/NEJMoa2201445
  20. Brandon M, Baldi P, Wallace DC. Mitochondrial mutations in cancer. Oncogene. 2006;25(34):4647–4662. doi: 10.1038/sj.onc.1209607
  21. Kopinski PK, Singh LN, Zhang S, et al. Mitochondrial DNA variation and cancer. Nat Rev Cancer. 2021;21(7):431–445. doi: 10.1038/s41568-021-00358-w
  22. Jiménez-Morales S, Pérez-Amado CJ, Langley E, Hidalgo-Miranda A. Overview of mitochondrial germline variants and mutations in human disease: focus on breast cancer (review). Int J Oncol. 2018;53(3):923–936. doi: 10.3892/ijo.2018.4468
  23. Weerts MJA, Sleijfer S, Martens JWM. The role of mitochondrial DNA in breast tumors. Drug Discov Today. 2019;24(5):1202–1208. doi: 10.1016/j.drudis.2019.03.019
  24. Salas A, Yao YG, Macaulay V, et al. A critical reassessment of the role of mitochondria in tumorigenesis. PLoS Med. 2005;2(11):e296. doi: 10.1371/journal.pmed.0020296
  25. Baysal B. Mitochondria: more than mitochondrial DNA in cancer. PLoS Med. 2006;3(3):e156. doi: 10.1371/journal.pmed.0030156
  26. Zanssen S, Schon EA. Mitochondrial DNA mutations in cancer. PLoS Med. 2005;2(11):e401. doi: 10.1371/journal.pmed.0020401
  27. Elliott RL, Jiang XP, Head JF. Mitochondria organelle transplantation: introduction of normal epithelial mitochondria into human cancer cells inhibits proliferation and increases drug sensitivity. Breast Cancer Res Treat. 2012;136(2):347–354. doi: 10.1007/s10549-012-2283-2
  28. DiMauro S, Schon EA. Mitochondrial DNA mutations in human disease. Am J Med Genet. 2001;106(1):18–26. doi: 10.1002/ajmg.1392
  29. McFarland R, Elson JL, Taylor RW, et al. Assigning pathogenicity to mitochondrial tRNA mutations: when ‘definitely maybe’ is not good enough. Trends Genet. 2004;20(12):591–596. doi: 10.1016/j.tig.2004.09.014
  30. Canter JA, Kallianpur AR, Parl FF, Millikan RC. Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African–American women. Cancer Res. 2005;65(17):8028–8033. doi: 10.1158/0008-5472.CAN-05-1428
  31. Salas A, García-Magariños M, Logan I, Bandelt H-J. The saga of the many studies wrongly associating mitochondrial DNA with breast cancer. BMC Cancer. 2014;14:659. doi: 10.1186/1471-2407-14-659
  32. Czarnecka AM, Krawczyk T, Plak K, et al. Mitochondrial genotype and breast cancer predisposition. Oncol Rep. 2010;24(6):1521–1534. doi: 10.3892/or-00001014
  33. Tommasi S, Favia P, Weigl S, et al. Mitochondrial DNA variants and risk of familial breast cancer: an exploratory study. Int J Oncol. 2014;44(5):1691–1698. doi: 10.3892/ijo.2014.2324
  34. Tipirisetti NR, Govatati S, Pullari P, et al. Mitochondrial control region alterations and breast cancer risk: a study in south Indian population. PLoS One. 2014;9(1):e85363. doi: 10.1371/journal.pone.0085363
  35. Yacoubi Loueslati B, Troudi W, Cherni L, et al. Germline HVR-II mitochondrial polymorphisms associated with breast cancer in Tunisian women. Genet Mol Res. 2010;9(3):1690–1700. doi: 10.4238/vol9-3gmr778
  36. Mosquera-Miguel A, Álvarez-Iglesias V, Carracedo Á, et al. Is mitochondrial DNA variation associated with sporadic breast cancer risk? Cancer Res. 2008;68(2):623–625. doi: 10.1158/0008-5472.CAN-07-2385
  37. Bai R-K, Leal SM, Covarrubias D, et al. Mitochondrial genetic background modifies breast cancer risk. Cancer Res. 2007;67(10):4687–4694. doi: 10.1158/0008-5472.CAN-06-3554
  38. Fang H, Shen L, Chen T, et al. Cancer type-specific modulation of mitochondrial haplogroups in breast, colorectal and thyroid cancer. BMC Cancer. 2010;10:421. doi: 10.1186/1471-2407-10-421
  39. Darvishi K, Sharma S, Bhat AK, et al. Mitochondrial DNA G10398A polymorphism imparts maternal Haplogroup N a risk for breast and esophageal cancer. Cancer Lett. 2007;249(2):249–255. doi: 10.1016/j.canlet.2006.09.005
  40. Gazi N, Rahman A, Karim MM, et al. Breast cancer risk associated mitochondrial NADH-dehydrogenase subunit-3 (ND3) polymorphisms (G10398A and T10400C) in Bangladeshi women. J Med Genet Genomics. 2011;3(8):131–135. doi: 10.5897/JMGG.9000007
  41. Czarnecka AM, Krawczyk T, Zdrożny M, et al. Mitochondrial NADH-dehydrogenase subunit 3 (ND3) polymorphism (A10398G) and sporadic breast cancer in Poland. Breast Cancer Res Treat. 2010;121(2):511–518. doi: 10.1007/s10549-009-0358-5
  42. Tengku Baharudin N, Jaafar H, Zainuddin Z. Association of mitochondrial DNA 10398 polymorphism in invasive breast cancer in Malay population of Peninsular Malaysia. Malaysian J Med Sci. 2012;19(1):36–42.
  43. Jahani MM, Azimi Meibody A, Karimi T, et al. An A10398G mitochondrial DNA alteration is related to increased risk of breast cancer, and associates with Her2 positive receptor. Mitochondrial DNA A DNA Mapp Seq Anal. 2020;31(1):11–16. doi: 10.1080/24701394.2019.1695788
  44. Covarrubias D, Bai RK, Wong LC, Leal SM. Mitochondrial DNA variant interactions modify breast cancer risk. J Hum Genet. 2008;53(10):924–928. doi: 10.1007/s10038-008-0331-x
  45. Ma L, Fu Q, Xu B, et al. Breast cancer-associated mitochondrial DNA haplogroup promotes neoplastic growth via ROS-mediated AKT activation. Int J Cancer. 2018;142(9):1786–1796. doi: 10.1002/ijc.31207
  46. Bonilla C, Bertoni B, Hidalgo PC, et al. Breast cancer risk and genetic ancestry: a case-control study in Uruguay. BMC Womens Health. 2015;15(1):1–10. doi: 10.1186/s12905-015-0171-8
  47. Francis A, Pooja S, Rajender S, et al. A mitochondrial DNA variant 10398G>A in breast cancer among South Indians: an original study with meta-analysis. Mitochondrion. 2013;13(6):559–565. doi: 10.1016/j.mito.2013.08.004
  48. Pisareva LF, Odintsova IN, Ivanov PM, Nikolaeva TI. Breast cancer incidence among indigenous peoples and newcomers in Sakha Republic (Yakutia). Siberian Journal of Oncology. 2007;(3):69–72. (In Russ).
  49. Zhou H, Nie K, Qiu R, et al. Generation and bioenergetic profiles of cybrids with East Asian mtDNA haplogroups. Oxid Med Cell Longev. 2017;2017:1062314. doi: 10.1155/2017/1062314
  50. Bunn CL, Wallace DC, Eisenstadt JM. Cytoplasmic inheritance of chloramphenicol resistance in mouse tissue culture cells. Proc Natl Acad Sci U S A. 1974;71(5):1681–1685. doi: 10.1073/pnas.71.5.1681
  51. Cruz-Bermúdez A, Vallejo CG, Vicente-Blanco RJ, et al. Enhanced tumorigenicity by mitochondrial DNA mild mutations. Oncotarget. 2015;6(15):13628–13643. doi: 10.18632/oncotarget.3698
  52. Sazonova MA, Sinyov VV, Ryzhkova AI, et al. Cybrid models of pathological cell processes in different diseases. Oxid Med Cell Longev. 2018;2018:4647214. doi: 10.1155/2018/4647214
  53. Kenney MC, Chwa M, Atilano SR, et al. Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: implications for population susceptibility to diseases. Biochim Biophys Acta. 2014;1842(2):208–219. doi: 10.1016/j.bbadis.2013.10.016
  54. Kazuno A, Munakata K, Nagai T, et al. Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics. PLoS Genet. 2006;2(8):e128. doi: 10.1371/journal.pgen.0020128
  55. Gómez-Durán A, Pacheu-Grau D, López-Gallardo E, et al. Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups. Hum Mol Genet. 2010;19(17):3343–3353. doi: 10.1093/hmg/ddq246
  56. Suissa S, Wang Z, Poole J, et al. Ancient mtDNA genetic variants modulate mtDNA transcription and replication. PLoS Genet. 2009;5(5):e1000474. doi: 10.1371/journal.pgen.1000474
  57. Mueller EE, Brunner SM, Mayr JA, et al. Functional differences between mitochondrial haplogroup T and haplogroup H in HEK293 cybrid cells. PLoS One. 2012;7(12):e52367. doi: 10.1371/journal.pone.0052367
  58. Pérez-Amado CJ, Tovar H, Gómez-Romero L, et al. Mitochondrial DNA mutation analysis in breast cancer: shifting from germline heteroplasmy toward homoplasmy in tumors. Front Oncol. 2020;10:572954. doi: 10.3389/fonc.2020.572954
  59. Ju YS, Alexandrov LB, Gerstung M, et al. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. Elife. 2014;3:e02935. doi: 10.7554/eLife.02935
  60. Nie H, Chen G, He J, et al. Mitochondrial common deletion is elevated in blood of breast cancer patients mediated by oxidative stress. Mitochondrion. 2016;26:104–112. doi: 10.1016/j.mito.2015.12.001
  61. Grasso D, Zampieri LX, Capelôa T, et al. Mitochondria in cancer. Cell Stress. 2020;4(6):114–146. doi: 10.15698/cst2020.06.221
  62. Rong Z, Tu P, Xu P, et al. The mitochondrial response to DNA damage. Front cell Dev Biol. 2021;9:669379. doi: 10.3389/fcell.2021.669379
  63. Lopez J, Tait SWG. Mitochondrial apoptosis: killing cancer using the enemy within. Br J Cancer. 2015;112(6):957–962. doi: 10.1038/bjc.2015.85

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. The electron transport chain of the inner membrane of mitochondria (adapted from [3]). CI–CV — complexes I–V; H+ — ionized hydrogen; NADH — reduced form of nicotinamidveadenine dinucleotide; NAD+ — oxidized form of nicotinamide adenine dinucleotide; Cyto C — cytochrome C; H2O — water; ADP — adenosine diphosphate; Pi — inorganic phosphorus; ATP — adenosine triphosphate; –ΔΨm — redox potential.

Download (329KB)
Indexing metadata
3. Fig. 2. Мap of the human mitochondrial genome [by 5–7]. HSP — heavy strand promoter; LSP — light strand promoter; control region — control region that controls the synthesis of RNA and DNA (localisation between 16024 and 576 bp); CSB1, CSB2, CSB3 — conservative blocks 1, 2 and 3; 7S DNA — short third strand of mtDNA in the D-loop region; OH — origin of mtDNA heavy strand replication; OL — origin of mtDNA light strand replication; TAS — termination-associated sequence; H, L — mtDNA heavy and light strands; T, P, E, L2, S2, H, R, G, K, D, S1, A, N, C, Y, W, M, Q, I, L1, V, F — tRNA genes; CYB — cytochrome B gene; ND6, ND5, ND4, ND3, ND2, ND1 — NADH-dehydrogenase subunit genes; CO3, CO2, CO1 — cytochrome oxidase subunit genes; RNR2 and RNR1 are mitochondrial 16S and 12S ribosomal RNA genes.

Download (202KB)
Indexing metadata
4. Fig. 3. Dynamics of changes in mitochondria during breast cancer development. The red background and red line show the increasing role of active glycolysis in cell energy production; green background and green line — reduced role of oxidative phosphorylation in cell energy production; red circles — mtDNA with a mutation; green circles are mtDNA germ lines.

Download (227KB)
Indexing metadata

Copyright (c) 2023 Tikhonov D.G., Vinokurov M.M., Kipriyanova N.S., Golubenko M.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies