Abstract:
:In the last decade, mitochondrial DNA (mtDNA) haplogroups have been associated with the occurrence of breast cancer. However, the underlying mechanism is not known. Combining a case-control study with a large cohort of women from Southern China with breast cancer and functional analyses with trans-mitochondrial technology, we demonstrate that the D5 haplogroup is associated with an increased risk of breast cancer [odds ratio (OR) = 2.789; 95% confidence interval (CI) [1.318, 5.901]; p = 0.007]. Furthermore, mitochondrial respiration, mitochondrial ATP content and membrane potential, were lower in both bone osteosarcoma and breast cancer cell models of cytoplasmic hybrids (cybrids) containing the mtDNA D5 haplogroup than in those with non-D5 haplogroups. Using in vitro and in vivo tumorigenicity assays, we found that cells with the D5 haplogroup were more susceptible to tumorigenesis compared to cells with non-D5 haplogroups. Mechanistically, the D5 haplogroup may promote tumorigenesis at least partially through activation of the v-AKT murine thymoma viral oncogene (AKT) via phosphorylation of threonine 308, which is mediated by increased reactive oxygen species generation in D5 cybrids. Our findings demonstrate that there is decreased mitochondrial function in cells with the D5 haplogroup compared to cells with non-D5 haplogroups, which may be associated with increased neoplastic growth in breast cancer.
journal_name
Int J Cancerjournal_title
International journal of cancerauthors
Ma L,Fu Q,Xu B,Zhou H,Gao J,Shao X,Xiong J,Gu Q,Wen S,Li F,Shen L,Chen G,Fang H,Lyu Jdoi
10.1002/ijc.31207subject
Has Abstractpub_date
2018-05-01 00:00:00pages
1786-1796issue
9eissn
0020-7136issn
1097-0215journal_volume
142pub_type
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