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.

Mitochondrial DNA Mutation Analysis in Breast Cancer: Shifting From Germline Heteroplasmy Toward Homoplasmy in Tumors

“…We found a higher frequency of the D haplogroup (12%) than in previously published works about the Mexican-Mestizo population (6.2%) (50,51). The D haplogroup has been associated with predisposition to breast cancer in the Chinese population and experimental data revealed that the D5 branch haplogroup promotes tumorigenesis through AKT activation, mediated by a high concentration of reactive oxygen species (ROS) (52,53). However, we need to include more patients and to perform a case-control analysis to determine whether the haplogroup D has clinical significance in Mexican women with breast cancer.…”

Highly‐expressed P2X7 receptor promotes growth and metastasis of human HOS/MNNG osteosarcoma cells via PI3K/Akt/GSK3β/β‐catenin and mTOR/HIF1α/VEGF signaling

“…Recently, PI3K/Akt has been associated with osteosarcoma progression and resistance to chemotherapeutic drugs. [39][40][41][42] BzATP increased Akt activity, but P2X7 receptor inhibition significantly reduced Akt phosphorylation in HOS/MNNG cells. Treatment with a PI3K inhibitor, LY294002, resulted in significantly reduced cell proliferation, migration and invasion.…”

“…The PI3K/Akt signaling cascade plays a critical role in tumor cell growth and bioenergetics, regulating aerobic glycolysis, cell cycle progression and autophagy. Recently, PI3K/Akt has been associated with osteosarcoma progression and resistance to chemotherapeutic drugs . BzATP increased Akt activity, but P2X7 receptor inhibition significantly reduced Akt phosphorylation in HOS/MNNG cells.…”

Evaluation of non‑coding region sequence variants and mitochondrial haplogroups as potential biomarkers of sporadic breast cancer in individuals of Sri Lankan Sinhalese ethnicity

“…Germline and somatic mutations in mtDNA have been studied in breast cancer in various populations across the world (26,29,30,47). Certain studies have suggested a positive correlation between specific D-loop mutations and haplogroups (48)(49)(50), and the risk of breast cancer. Therefore, mtDNA may serve as a potential biomarker for the early diagnosis of breast cancer, and its relevance may be dependent on ethnicity (21,51).…”

“…Mutations Patients Controls 1 73G, 150T, 195C, 240G, 263G, 315.1C, 16129A, 16266T, 16311C, 16318G, 16320T, 0 2 16362C, 16519C 2 73G, 195A, 263G, 315.1C, 489C, 523d, 524d, 16223T, 16519C 1 2 the Sri Lankan population, where a majority belonged to the M haplogroup followed by the N haplogroup and its derivatives (28). Other studies have reported an association between haplogroups and breast cancer, such as haplogroup D5 and M in the Chinese population (49,59,60) and haplogroup N in the Indian population (57,61). Whilst the Sinhalese population was not associated with a macro-haplogroup, the haplogroup M65a@16311 was observed in a number of patients and the haplogroup M30 was observed in a number of controls.…”