Mutations in mitochondrial DNA polymerase-γ promote breast tumorigenesis

Abstract

Decreased mitochondrial oxidative phosphorylation (OXPHOS) is one of the hallmarks of cancer. To date the identity of nuclear gene(s) responsible for decreased OXPHOS in tumors remains unknown. It is also unclear whether mutations in nuclear gene(s) responsible for decreased OXPHOS affect tumorigenesis. Polymerase γ (POLG) is the only DNA polymerase known to function in human mitochondria. Mutations in POLG are known to cause mtDNA depletion and decreased OXPHOS resulting in mtDNA depletion syndrome (MDS) in humans. We therefore sequenced all coding exons [2-23] and flanking intron/splice junctions of POLG in breast tumors. We found that the POLG gene was mutated in 63% of the breast tumors. We identified a total of 17 mutations across the POLG gene. Mutations were found in all three domains of POLG protein, including T251I (exonuclease domain), P587L (linker region) and E1143G (polymerase domain). We identified two novel mutations that include one silent (A703A) and one missense (R628Q) mutation in the evolutionarily conserved POLG linker region. Additionally, we identified three novel mutations in the intronic region. Our study also revealed that mtDNA was depleted in breast tumors. Consistently, mutant POLG when expressed in breast cancer cells induced depletion of mtDNA, decreased mitochondrial activity, decreased mitochondrial membrane potential, increased levels of reactive oxygen species (ROS), and increased matrigel invasion. Together, our study provides the first comprehensive analysis of the POLG gene mutation in human cancer and suggests a role for POLG in 1) decreased OXPHOS in cancers and 2) in promoting tumorigenicity.

Role of mitochondrial dysfunction in cancer progression

“…62 Depletion of mtDNA in breast cancer cells by expressing mutant mitochondrial DNA polymerase g increases Matrigel invasion. 64 In addition, chemical impairment of the mitochondrial respiratory chain in HepG2 cells enhances their migratory phenotype through the overexpression and secretion of amphiregulin by an autocrine or paracrine loop, 57 and overexpression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1a) to promote mitochondrial biogenesis in HepG2 cells can markedly repress cell migration through the upregulation of E-cadherin expression. 65,66 We also found that chemical impairment of the mitochondrial respiratory chain in human gastric cancer cells enhances cell migration through ROS-induced integrin b5 expression.…”

The importance of mitochondria in the tumourigenic phenotype: Gliomas as the paradigm (Review)

“…Previous work has also shown the importance of mTfam in cancer cells (86). Further, it has been shown that mutations in mtDNA polymerase Á promotes tumourigenesis in breast cancer (127). Moreover, ddC has also been noted to have sensitising effects with ionizing radiation.…”

Mitochondrial Markers for Cancer: Relevance to Diagnosis, Therapy, and Prognosis and General Understanding of Malignant Disease Mechanisms

“…Mutations in the POLG gene have been detected in breast cancers and are associated with mtDNA depletion in cancer cells [98]. The POLG gene contains a polymorphic CAG repeat of a dominant length of 10.…”