title: Mitochondrial DNA Repair through OGG1 Activity Attenuates Breast Cancer Progression and Metastasis.
abstract: Production of mitochondrial reactive oxygen species and integrity of mitochondrial DNA (mtDNA) are crucial in breast cancer progression and metastasis. Therefore, we evaluated the role of mtDNA damage in breast cancer by genetically modulating the DNA repair enzyme 8-oxoguanine DNA glycosylase (OGG1) in the PyMT transgenic mouse model of mammary tumorigenesis. We generated mice lacking OGG1 (KO), mice overexpressing human OGG1 subunit 1α in mitochondria (Tg), and mice simultaneously lacking OGG1 and overexpressing human OGG1 subunit 1α in mitochondria (KO/Tg). We found that Tg and KO/Tg mice developed significantly smaller tumors than KO and wild-type (WT) mice after 16 weeks. Histologic analysis revealed a roughly 2-fold decrease in the incidence of lung metastases in Tg mice (33.3%) compared to WT mice (62.5%). Furthermore, lungs from Tg mice exhibited nearly a 15-fold decrease in the average number of metastatic foci compared with WT mice (P ≤ 0.05). Primary tumors isolated from Tg mice also demonstrated reduced total and mitochondrial oxidative stress, diminished mtDNA damage, and increased mitochondrial function. Targeting hOGG1 to the mitochondria protected cells from mtDNA damage, resulting in downregulation of HIF1α and attenuated phosphorylation of Akt. Collectively, we demonstrate proof of concept that mtDNA damage results in breast cancer progression and metastasis in vivo. Moreover, our findings offer new therapeutic strategies for modulating the levels of mtDNA repair enzymes to delay or stall metastatic progression.
authors.affiliation: Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: Larysa V
authors.initials: LV
authors.lastname: Yuzefovych
authors.affiliation: Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Kahn
authors.affiliation: Department of Comparative Medicine, College of Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: Michele A
authors.initials: MA
authors.lastname: Schuler
authors.affiliation: Department of Medical Biochemistry, University of Oslo and Centre of Molecular Biology and Neuroscience, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Ritu
authors.initials: R
authors.lastname: Arora
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Wilson
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, Alabama. lrachek@southalabama.edu.
authors.forename: Lyudmila I
authors.initials: LI
authors.lastname: Rachek
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis
chemical_list: D004272:DNA, Mitochondrial; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human