Mitochondrial DNA Repair through OGG1 Activity Attenuates Breast Cancer Progression and Metastasis
Authors: Michele A Schuler
Ming Tan
Glenn L Wilson
Lars Eide
Ritu Arora
Larysa V Yuzefovych
Andrea G Kahn
Lyudmila I Rachek
Journal: Cancer Research (2016)
Discipline: CLINICAL MEDICINE
Keywords: mitochondrial reactive oxygen species; mitochondrial DNA; breast cancer progression; metastasis; DNA repair enzyme
Affiliations: Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, Alabama., Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama., Department of Comparative Medicine, College of Medicine, University of South Alabama, Mobile, Alabama., Department of Medical Biochemistry, University of Oslo and Centre of Molecular Biology and Neuroscience, University of Oslo and Oslo University Hospital, Oslo, Norway., Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama., Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, Alabama., Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, Alabama. .

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. 

Retracted: No

PubPeer comments:
 Figure 2A. * Red boxes: Two lanes in the Tg panel appear to overlap with two lanes in the KO Tg panel, albeit stretched differently. ![file] , 
 2021 correction. https: cancerres.aacrjournals.org content 81 11 3144 In the original version of this article (1), there are errors in Figs. 2A and 2E. Specifically, in Fig. 2A, the Western blot image of the WT TG panel partially overlaps with that of the KO TG panel. In addition, the Southern blot image in Fig. 2E was erroneously spliced. The errors have been corrected in the latest online HTML and PDF versions of the article. The authors regret these errors. Reference 1.u21b5Yuzefovych LV, Kahn AG, Schuler MA, Eide L, Arora R, Wilson GL, et al. Mitochondrial DNA repair through OGG1 activity attenuates breast cancer progression and metastasis. Cancer Res 2016;76:30u20134. ,