Mitochondrial DNA Repair through OGG1 Activity Attenuates Breast Cancer Progression and Metastasis
| Autor: | Larysa V. Yuzefovych, Ritu Arora, Michele Schuler, Lars Eide, Ming Tan, Glenn L. Wilson, Lyudmila I. Rachek, Andrea G. Kahn |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Cancer Research Mitochondrial DNA Pathology medicine.medical_specialty DNA Repair DNA repair Breast Neoplasms Mice Transgenic Mitochondrion Biology medicine.disease_cause DNA Mitochondrial DNA Glycosylases Metastasis Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Neoplasm Metastasis Mice Knockout medicine.disease Disease Models Animal 030104 developmental biology Oncology Mitochondrial DNA repair DNA glycosylase 030220 oncology & carcinogenesis Disease Progression Cancer research Female Oxidative stress |
| Zdroj: | Cancer Research. 76:30-34 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-15-0692 |
| Popis: | 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. Cancer Res; 76(1); 30–34. ©2015 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|