Breast cancer-associated mitochondrial DNA haplogroup promotes neoplastic growth via ROS-mediated AKT activation.

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 Cancer

authors

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 J

doi

10.1002/ijc.31207

subject

Has Abstract

pub_date

2018-05-01 00:00:00

pages

1786-1796

issue

9

eissn

0020-7136

issn

1097-0215

journal_volume

142

pub_type

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